Novel hybrid galactoside inhibitor of galectins

ABSTRACT

The present invention relates to a compound of the general formula (1). The compound of formula (1) is suitable for use in a method for treating a disorder relating to the binding of a galectin, such as galectin-3 to a ligand in a mammal, such as a human. Furthermore the present invention concerns a method for treatment of a disorder relating to the binding of a galectin, such as galectin-3 to a ligand in a mammal, such as a human.

TECHNICAL FIELD

The present invention relates to novel compounds, the use of saidcompounds as medicament and for the manufacture of a medicament fortreating a disorder relating to the binding of a galectin, such asgalectin-3 to a ligand in a mammal, such as a human, in particular forthe treatment of pulmonary fibrosis, such as Idiopathic pulmonaryfibrosis in mammals. The invention also relates to pharmaceuticalcompositions comprising said novel compounds.

BACKGROUND ART

Galectins are proteins with a characteristic carbohydrate recognitiondomain (CRD) (Barondes et al., 1994; Leffler et al., 2004). This is atightly folded β-sandwich of about 130 amino acids (about 15 kDa) withthe two defining features 1) a β-galactose binding site and 2)sufficient similarity in a sequence motif of about seven amino acids,most of which (about six residues) make up the β-galactose binding site.However, sites adjacent to the β-galactose site are required for tightbinding of natural saccharides and different preferences of these givegalectins different fine specificity for natural saccharides.

The recent completion of the human, mouse and rat genome sequencesreveal about 15 galectins and galectin-like proteins in one mammaliangenome with slight variation between species (Leffler et al., 2004)

Galectin subunits can contain either one or two CRDs within a singlepeptide chain. The first category, mono-CRDs galectins, can occur asmonomers or dimers (two types) in vertebrates. The by far best studiedgalectins are the dimeric galectin-1, and galectin-3 that is a monomerin solution but may aggregate and become multimeric upon encounter withligands (Leffler et al., 2004). These were the first discoveredgalectins and are abundant in many tissues.

There are now over 3500 publications on galectins in PubMed, with most,as mentioned above, about galectins-1 (>900) and -3 (>1600). Strongevidence suggests roles for galectins in e.g. inflammation and cancer,and development recently reviewed in a special issue (Leffler (editor),2004b).

Galectins are synthesized as cytosolic proteins, without a signalpeptide on free ribosomes. Their N-terminus is acetylated, a typicalmodification of cytosolic proteins, and they reside in the cytosol for along time (not typical of secreted proteins). From there they can betargeted to the nucleus, specific cytososlic sites, or secreted (inducedor constitutively) by a non-classical (non-ER-Golgi) pathway, as yetunknown, but possibly similar to the export of e.g. IL-1 (Leffler etal., 2004). They can also function in all these compartments; forgalectin-3, solid evidence published in well respected journals supportroles in RNA splicing in the nucleus, inhibition of apoptosis in thecytosol, and a variety of extracellular effects on cell signaling andadhesion (Leffler (editor), 2004b). Galectin-7 and -12 also act in thecytosol by enhancing apoptosis and regulating the cell cycle anddifferentiation in certain cells (Hsu and Liu in Leffler (editor),2004b). Most galectins act also extracellularly by cross-linkingglycoproteins (e.g. laminin, integrins, and IgE receptors) possiblyforming supramolecular ordered arrays (Brewer et al., 2002) and maythereby modulate cell adhesion and induce intracellular signals. Relatedto this, recent years have seen the emergence of a molecular mechanismof these galectin functions involving a formation of microdomains(lattices) within membranes, (Dam et al., 2008; Garner et al., 2008)which in turn affects intracellular trafficking and cell surfacepresentation of glycoprotein receptors. (Delacour et al., 2007; Lau etal., 2007; Lau et al. 2008) This has been documented in cell culture, innull mutant mice, (Blois et al., 2007; Gedronneau et al., 2008; Thijssenet al., 2007; Toscano et al., 2007; Saegusa et al., 2009) and animalstreated with galectin (Blois et al., 2007; Perone et al., 2009) orgalectin inhibitors. (John et al., 2003; Pienta et al., 1995; Glinsky etal., 1996)

Potential Therapeutic Use of Galectin-3 Inhibitors

Galectin-3 has been implicated in diverse phenomena and, hence,inhibitors may have multiple uses. It is easy to perceive this as a lackof specificity or lack of scientific focus. Therefore, the analogy withaspirin and the cyclooxygenases (COX-I and II) is useful. The COXsproduce the precursor of a wide variety of prostaglandins and, hence,are involved in a diverse array of biological mechanisms. Theirinhibitors, aspirin and other NSAIDs (nonsteroid anti-inflammatorydrugs), also have broad and diverse effects. Despite this, theseinhibitors are very useful medically, and they have several differentspecific utilities.

So if galectins, like COXs, are part of some basic biological regulatorymechanism (as yet unknown), they are likely to be ‘used by nature’ fordifferent purpose in different contexts. Galectin inhibitors, likeNSAIDs, are not expected to wipe out the whole system, but to tilt thebalance a bit.

Inhibition of Inflammation

A pro-inflammatory role of galectin-3 is indicated by its induction incells at inflammatory sites, a variety of effects on immune cells (e.g.oxidative burst in neutrophils and chemotaxis in monocytes), anddecrease of the inflammatory response, mainly in neutrophils andmacrophages, in null mutant mice (in Leffler (editor), 2004b). Moreover,knock-out mice of Mac-2BP, a galectin-3 ligand, have increasedinflammatory responses (Trahey et al., 1999). Importantly, recentstudies have identified galectin-3 as a key rate-limiting factor inmacrophage M2 differentiation and myofibroblast activation, whichinfluences the development of fibrosis (Mackinnon et al., 2008;Mackinnon et al., 2012).

Inflammation is a protective response of the body to invading organismsand tissue injury. However, if unbalanced, frequently it is alsodestructive and occurs as part of the pathology in many diseases.Because of this, there is great medical interest in pharmacologicalmodulation of inflammation. A galectin-3 inhibitor is expected toprovide an important addition to the arsenal available for this.

Treatment of Fibrosis-Related Conditions

The idea of a possible role of galectin-3 in fibrosis comes from celland ex vivo studies on macrophage differentiation (Mackinnon et al.,2008), as well as from in vivo studies on macrophage differentiation andmyofibroblast activation (Mackinnon et al., 2012). Briefly, thehypothesis is as follows: Galectin-3 has been shown to prolong cellsurface residence and thus enhance responsiveness of the TGF-β receptor(Partridge et al., 2004), which in turn regulates alternative macrophagedifferentiation into M2 macrophages and myofibroblast activation.

Hence, as galectin-3 is a good candidate for being an endogenousenhancer of TGF-β signaling and alternative macrophage differentiationand myofibroblast activation, galectin-3 inhibitors may be very usefulin treating fibrosis and adverse tissue remodeling.

Treatment of Cancer

A large number of immunohistochemical studies show changed expression ofcertain galectins in cancer (van den Brule et. al. and Bidon et al. inLeffler (editor), 2004b) and for example galectin-3 is now anestablished histochemical marker of thyroid cancer. The direct evidencefor a role of galectin-3 in cancer comes from mouse models, mainly byRaz et al, but also others (in Leffler (editor), 2004b). In paired tumorcell lines (with decreased or increased expression of galectin-3), theinduction of galectin-3 gives more tumors and metastasis and suppressionof galectin-3 gives less tumors and metastasis. Galectin-3 has beenproposed to enhance tumor growth by being anti-apoptotic, promoteangiogenesis, or to promote metastasis by affecting cell adhesion. Fromthe above it is clear that inhibitors of galectin-3 might have valuableanti-cancer effects. Indeed, saccharides claimed but not proven toinhibit galectin-3 have been reported to have anti-cancer effects. Inour own study a fragment of galectin-3 containing the CRD inhibitedbreast cancer in a mouse model by acting as a dominant negativeinhibitor (John et al., 2003). More recently, inhibition of galectin-3with small molecules have been demonstrated to indeed greatly enhancetumor cell sensitivity towards radiation and standard pro-apoptoticdrugs in cell assays and ex vivo (Lin et al., 2009), as well as in vivo(Glinsky et al., 2009).

Also galectin-1 is frequently over-expressed in low differentiatedcancer cells, and galectin-9 or its relatives galectin-4 and galectin-8may be induced in specific cancer types (Huflejt and Leffler, 2004;Leffler (editor), 2004b). Galectin-1 induces apoptosis in activatedT-cells and has a remarkable immunosuppressive effect on autoimmunedisease in vivo (Rabinovich et al; and Pace et al. in Leffler (editor),2004b). Therefore, the over-expression of these galectins in cancersmight help the tumor to defend itself against the T-cell response raisedby the host.

Null mutant mice for galectins-1 and -3 have been established many yearsago (Poirier, 2002). These are healthy and reproduce apparently normallyin animal house conditions. However, recent studies have revealed subtlephenotypes in function of neutrophils and macrophages (as describedabove) and in bone formation for galectin-3 null mutants, and in nerveand muscle cell regeneration/differentiation for the galectin-1 nullmutants (Leffler et al., 2004; Poirier, 2002; Watt in Leffler (editor),2004b). Recently galectin-7 and galectin-9 null mutant mice have beengenerated and are also grossly healthy in animal house conditions, buthave not yet been analyzed in detail. The differences in site ofexpression, specificity and other properties make it unlikely thatdifferent galectins can replace each other functionally. Theobservations in the null mutant mice would indicate that galectins arenot essential for basic life supporting functions as can be observed innormal animal house conditions. Instead they may be optimizers of normalfunction and/or essential in stress conditions not found in animal houseconditions. The lack of strong effect in null mutant mice may makegalectin inhibitors more favorable as drugs. If galectin activitycontributes to pathological conditions as suggested above but less tonormal conditions, then inhibition of them will have less unwanted sideeffects.

Treatment of Angiogenesis

Vascular endothelial growth factors (VEGFs) signaling through VEGFreceptor-2 (VEGFR-2) is the primary angiogenic pathway. Studies havebeen published demonstrating that both galectin-1 (Gal-1) and galectin-3(Gal-3) are important modulators for VEGF/VEGFR-2 signaling pathway. Ithas also been published that a galectin inhibitor, TDX, is expected haveefficacy against pathological angiogenesis. (Chen 2012)

Known Inhibitors Natural Ligands

Solid phase binding assays and inhibition assays have identified anumber of saccharides and glycoconjugates with the ability to bindgalectins (reviewed by Leffler, 2001 and Leffler et al., 2004). Allgalectins bind lactose with a K_(d) of 0.5-1 mM. The affinity ofD-galactose is 50-100 times lower. N-Acetyllactosamine and relateddisaccharides bind about as well as lactose, but for certain galectins,they can bind either worse or up to 10 times better. The best smallsaccharide ligands for galectin-3 were those carrying blood groupAdeterminants attached to lactose or LacNAc-residues and were found tobind up to about 50 times better than lactose. Galectin-1 shows nopreference for these saccharides.

Larger saccharides of the polylactosamine type have been proposed aspreferred ligands for galectins. In solution, usingpolylactosamine-carrying glycopeptides, there was evidence for this forgalectin-3, but not galectin-1 (Leffler and Barondes, 1986). A modifiedplant pectin polysaccharide has been reported to bind galectin-3 (Pientaet al., 1995).

The above-described natural saccharides that have been identified asgalectin-3 ligands are not suitable for use as active components inpharmaceutical compositions, because they are susceptible to acidichydrolysis in the stomach and to enzymatic degradation. In addition,natural saccharides are hydrophilic in nature, and are not readilyabsorbed from the gastrointestinal tract following oral administration.

Galectin Specificity

The studies of galectin specificity using inhibition by small naturalsaccharides mentioned above indicated that all galectins bound lactose,LacNAc and related disaccharides, but that galectin-3 bound certainlonger saccharides much better (Leffler and Barondes, 1986). Theselonger saccharides were characterized by having an additional sugarresidue added to the C-3 position of galactose (in e.g. lactose orLacNAc) that bound an extended binding groove. The shape of this groovevaries between galectins, suggesting that the same extensions would notbe bound equally by the different galectins.

Synthetic Inhibitors

Saccharides coupled to amino acids with anti-cancer activity were firstidentified as natural compounds in serum, but subsequently, syntheticanalogues have been made (Glinsky et al., 1996). Among them, those withlactose or galactose coupled to the amino acid inhibit galectins, butonly with about the same potency as the corresponding underivatizedsugar. A chemically modified form of citrus pectin (Platt and Raz, 1992)that inhibits galectin-3 shows anti-tumor activity in vivo (Pienta etal., 1995; Nangia-Makker et al., 2002).

Cluster molecules having up to four lactose moieties showed a strongmultivalency effect when binding to galectin-3, but not to galectin-1and galectin-5 (Vrasidas et al., 2003). Cyclodextrin-based glycoclusterswith seven galactose, lactose, or N-acetyllactosamine residues alsoshowed a strong multivalency effect against galectin-3, but less soagainst galectins-1 and -7 (André et al., 2004). Starburst dendrimers(André et al., 1999) and glycopolymers (Pohl et al., 1999; David et al.,2004), made polyvalent in lactose-residues, have been described asgalectin-3 inhibitors with marginally improved potency as compared tolactose. The aforementioned synthetic compounds that have beenidentified as galectin-3 ligands are not suitable for use as activecomponents in pharmaceutical compositions, because they are hydrophilicin nature and are not readily absorbed from the gastrointestinal tractfollowing oral administration.

Natural oligosaccharides, glycoclusters, glycodendrimers, andglycopolymers described above are too polar and too large to be absorbedand in some cases are large enough to produce immune responses inpatients. Furthermore, they are susceptible to acidic hydrolysis in thestomach and to enzymatic hydrolysis. Thus, there is a need for smallsynthetic molecules

Thiodigalactoside is known to be a synthetic and hydrolytically stable,yet polar inhibitor, approximately as efficient as N-acetyllactosamine(Leffler and Barondes, 1986). N-Acetyllactosamine derivatives carryingaromatic amides or substituted benzyl ethers at C-3′ have beendemonstrated to be highly efficient inhibitors of galectin-3, withunprecedented IC₅₀ values as low as 4.8 μM, which is a 20-foldimprovement in comparison with the natural N-acetyllactosaminedisaccharide (Sörme et al., 2002; Sörme et al., 2003b). Thesederivatives are less polar overall, due to the presence of the aromaticamido moieties and are thus more suitable as agents for the inhibitionof galectins in vivo. Furthermore, C3-triazolyl galactosides have beendemonstrated to be as potent inhibitors as the corresponding C3-amidesof some galectins. Hence, any properly structured galactoseC3-substituent may confer enhanced galectin affinity.

However, the C3-amido- and C3-triazolyl-derivatised compounds are stillsusceptible to hydrolytic degradation in vivo, due to the presence of aglycosidic bond in the galactose and N-acetyllactosamine saccharidemoiety and, although they are potent small molecule inhibitors ofgalectin-3, even further improved affinity and stability is desirable.Accordingly, inhibitors based on 3,3′-diamido- or3,3′-ditriazolyl-derivatization of thiodigalactoside have beendeveloped, (Cumpstey et al., 2005b; Cumpstey et al., 2008; Salameh etal., 2010; WO/2005/113569 and US2007185041; WO/2005/113568, U.S. Pat.No. 7,638,623 B2) which lack 0-glycosidic hydrolytically andenzymatically labile linkages. These inhibitors also displayed superioraffinity for several galectins (down to Kd in the low nM range).Nevertheless, although displaying high affinity for galectins, the3,3′-derivatized thiodigalactosides still comprise a disadvantage intheir multistep synthesis involving double inversion reaction to reachat 3-N-derivatized galactose building blocks. Furthermore, cyclohexanereplacement of one galactose ring in thiodigalactoside has beenevidenced to mimic the galactose ring and hence to provide galectin-1and -3 inhibitors with efficiency approaching those of the diamidoandditriazolyl-thiodigalactoside derivatives (WO/2010/126435). Replacementof a D-galactopyranose unit with a substituted cyclohexane decreasespolarity and most likely also metabolic susceptibility, thus improvingdrug-like properties.

Some earlier described compounds have the following general formulas

as described in WO/2005/113568, and

as described in WO/2005/113569, in which R^(I) can be a D-galactose, and

as described in WO/2010/126435.

Thus, due to the less than optimal manufacturing processes towardsgalactose 3-Nderivatization (Z and Y are preferably nitrogen atoms)involving double inversion reactions at a complex protectedD-galactopyranose derivative of the compounds of the prior art, there isstill a considerable need within the art of inhibitors againstgalectins, in particular of galectin-1 and galectin-3.

In recently published US20140099319 and WO2014067986 are disclosed acompound of formula

having fluorine in the meta position on both the phenyl rings inrelation to the triazole rings. This compound (also referred to asBis-(3-deoxy-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)β-D-galactopyranosyl)sulfane) has been shown to be a promising drug candidate for lungfibrosis, and in particular is very selective on galectin-3 with highaffinity.

SUMMARY OF THE INVENTION

The compounds of the present invention have very high selectivity andaffinity for Gal3, in particular have high selectivity over Gal-1, andare considered potent drug candidates.

Several of these compounds have good solubility which is important formaking pharmaceutical formulations.

In a broad aspect the present invention relates to a compound of formula(1)

Wherein

A is selected from

wherein R₁-R₃ are independently selected from hydrogen (H), fluorine,methyl optionally substituted with a fluorine (F), and OCH₃ optionallysubstituted with a F;R₄ and R₅ are independently selected from H, F, Cl and methyl;R₆ is selected from C₁₋₆ alkyl, branched C₃₋₆ alkyl and C3-C7cycloalkyl;R₇ is selected from aryl, such as phenyl, naphthyl and anthracenyl,optionally substituted with a F, Cl, methyl optionally substituted witha F, and OCH₃ optionally substituted with a F;

B is selected from

wherein R₈-R₁₂ are independently selected from H, F, methyl optionallysubstituted with a fluorine (F), and OCH₃ optionally substituted with aF;R₁₃-R₁₆ are independently selected from H, F, methyl optionallysubstituted with a F, and OCH₃ optionally substituted with a F;R₁₇ is selected from C₁₋₆ alkyl, branched C₃₋₆ alkyl and C₃₋₇cycloalkyl;R₁₈ is selected from aryl, such as phenyl, naphthyl and anthracenyl,optionally substituted with a F, Cl, methyl optionally substituted witha F, and OCH₃ optionally substituted with a F; ora pharmaceutically acceptable salt or solvate thereof.

In another aspect the present invention relates to a compound of formula(1) for use as a medicine.

In a further aspect the present invention relates to a pharmaceuticalcomposition comprising the compound of formula (1) and optionally apharmaceutically acceptable additive, such as carrier or excipient.

In a still further aspect the present invention relates to a compound offormula (1) for use in a method for treating a disorder relating to thebinding of a galectin, such as galectin-3 to a ligand in a mammal, suchas a human.

In a further aspect the present invention relates to a method fortreatment of a disorder relating to the binding of a galectin, such asgalectin-3, to a ligand in a mammal, such as a human, wherein atherapeutically effective amount of at least one compound of formula (1)is administered to a mammal in need of said treatment.

In a still further aspect the present invention relates to a process ofpreparing a compound of formula 1 or a pharmaceutically acceptable saltor solvate thereof comprising the steps a1-a6:

a1) reacting a compound I with acetic anhydride and pyridine in an inertsolvent such as pyridine at room temperature to provide a compound ofthe formula II;a2) reacting a compound II with the corresponding salicylaldehyde in theprescence of p-toluenesulfonylazide and CuI in an inert solvent, such asTHF, to give a sulfonimide intermediate, this intermediate is isolatedusing aqueous workup followed by treatment with a base, such as sodiummethoxide in a solvent, such as methanol followed by treatment withdowex to adjust to pH 7 followed by removal of solvent to give acoumarine intermediate without acetoxy groups, and this intermediate isthen treated with acetic anhydride using an organic base such aspyridine to give to give the compound of formula III;a3) reacting the compound of the formula III with ZnBr and acetylbromide in an inert solvent, such as CH₂Cl₂, and optionally isolatingintermediate and washing with aqueous NaHCO₃, and further reacting withtriisopropylsilanethiol in an inert solvent, such as acetone, to providethe compound of formula IV;a4) reacting the compound of formula IV with a compound of formula Vusing a reagent, such as tetrabutylammoniumfluoride, in an inertsolvent, such as acetonitrile, to provide the compound of formula VI;a5) reacting the compound of the formula VI with sodium methoxide inmethanol to provide the compound of the formula VII;a6) reacting the compound of formula VII with a compound of formula VIIIin an inert solvent, such as DMF, using a base, such asdiisopropylamine, catalyzed by CuI to provide the compound of theformula IX.

Further Embodiments 1-20

-   -   1. A compound of formula (1)

-   -   Wherein    -   A is selected from

-   -   wherein R₁-R₃ are independently selected from hydrogen (H),        fluorine, methyl optionally substituted with a fluorine (F), and        OCH₃ optionally substituted with a F;    -   R₄ and R₅ are independently selected from H, F, Cl and methyl;    -   R₆ is selected from C₁₋₆ alkyl, branched C₃₋₆ alkyl and C₃₋₇        cycloalkyl;    -   R₇ is selected from phenyl optionally substituted with a H, F,        Cl, methyl optionally substituted with a F, and OCH₃ optionally        substituted with a F, 1-Naphtyl optionally substituted with a H,        F, Cl, methyl optionally substituted with a F, and OCH₃        optionally substituted with a F, or a 2-Naphtyl optionally        substituted with a H, F, Cl, methyl optionally substituted with        a F, and OCH₃ optionally substituted with a F;    -   B is selected from

-   -   wherein R₈-R₁₂ are independently selected from H, F, methyl        optionally substituted with a fluorine (F), and OCH₃ optionally        substituted with a F;    -   R₁₃-R₁₆ are independently selected from H, F, methyl optionally        substituted with a F, and OCH₃ optionally substituted with a F;    -   R₁₇ is selected from C₁₋₆ alkyl, branched C₃₋₆ alkyl and C₃₋₇        cycloalkyl;    -   R₁₈ is selected from phenyl optionally substituted with a H, F,        Cl, methyl optionally substituted with a F, and OCH₃ optionally        substituted with a F, 1-Naphtyl optionally substituted with a H,        F, Cl, methyl optionally substituted with a F, and OCH₃        optionally substituted with a F, or a 2-Naphtyl optionally        substituted with a H, F, Cl, methyl optionally substituted with        a F, and OCH₃ optionally substituted with a F; or    -   a pharmaceutically acceptable salt or solvate thereof; with the        proviso that A and B cannot be identical.    -   2. The compound of embodiment 1 wherein A is selected from        formula 2.    -   3. The compound of embodiment 1 wherein A is selected from        formula 2 and B is selected from formula 6.    -   4. The compound of embodiment 3 wherein R₁-R₃ are independently        selected from H or F, and wherein R₈-R₁₂ are independently        selected from H or F.    -   5. The compound of embodiment 1 wherein A is selected from        formula 2 and B is selected from 7.    -   6. The compound of embodiment 5 wherein R₁-R₃ are independently        selected from H or F, and wherein R₁₃-R₁₄ are both F, and        R₁₅-R₁₆ are both H.    -   7. The compound of embodiment 6 wherein R₁ is H, R₂ is H, and R₃        is F.    -   8. The compound of embodiment 6 wherein R₁-R₃ are F.    -   9. The compound of embodiment 1 wherein A is selected from        formula 2 and B is selected from 8.    -   10. The compound of embodiment 9 wherein R₁-R₃ are independently        selected from H or F, and R₁₇ is C₁₋₅ alkyl, such as methyl or        tert-butyl.    -   11. The compound of embodiment 9 or 10 wherein R₁-R₃ are all F,        and R₁₇ is tert-butyl.    -   12. The compound of embodiment 1 wherein A is selected from        formula 2 and B is selected from 9.    -   13. The compound of embodiment 12 wherein R₁-R₃ are        independently selected from H or F, and R₁₈ is selected from        phenyl substituted with four F and one OCH₃, such as        2,3,5,6-tetrafluoro-4-methoxy-phenyl; 1-Naphtyl and 2-Naphtyl.    -   14. The compound of embodiment 12 wherein R₁-R₃ are all F, and        R₁₈ is selected from 2,3,5,6-tetrafluoro-4-methoxy-phenyl.    -   15. The compound of any one of embodiments 1-14 for use as a        medicine.    -   16. A pharmaceutical composition comprising the compound of any        one of the previous embodiments and optionally a        pharmaceutically acceptable additive, such as carrier or        excipient.    -   17. The compound of any one of the embodiments 1-14 for use in a        method for treating a disorder relating to the binding of a        galectin, such as galectin-3 to a ligand in a mammal, such as a        human.    -   18. The compound for use according to embodiment 17, wherein        said disorder is selected from the group consisting of        inflammation; fibrosis, such as pulmonary fibrosis, liver        fibrosis, kidney fibrosis, ophtalmological fibrosis and fibrosis        of the heart; septic shock; cancer; autoimmune diseases;        metabolic disorders; heart disease; heart failure; pathological        angiogenesis, such as ocular angiogenesis or a disease or        condition associated with ocular angiogenesis, e.g.        neovascularization related to cancer; and eye diseases, such as        age-related macular degeneration and corneal neovascularization.    -   19. A method for treatment of a disorder relating to the binding        of a galectin, such as galectin-3, to a ligand in a mammal, such        as a human, wherein a therapeutically effective amount of at        least one compound according to any one of the embodiments 1-14        is administered to a mammal in need of said treatment.    -   20. The method of embodiment 19, wherein said disorder is        selected from the group consisting of inflammation; fibrosis,        such as pulmonary fibrosis, liver fibrosis, kidney fibrosis,        ophtalmological fibrosis and fibrosis of the heart; septic        shock; cancer; autoimmune diseases; metabolic disorders; heart        disease; heart failure; pathological angiogenesis, such as        ocular angiogenesis or a disease or condition associated with        ocular angiogenesis, e.g. neovascularization related to cancer;        and eye diseases, such as age-related macular degeneration and        corneal neovascularization.

Further Embodiments 21-41

-   -   21. A compound of formula (I)

wherein R_(a)-R_(f) are independently selected from fluorine orhydrogen, and at least three of a₁-R_(f) are F and the remaining are H,or all of R_(a)-R_(f) are F.

-   -   22. The compound of embodiment 21 wherein at least three of        R_(a)-R_(f) are F and the remaining are H.    -   23. The compound of embodiment 21 wherein at least four of        R_(a)-R_(f) are F and the remaining are H.    -   24. The compound of embodiment 21 or 22 wherein three of        R_(a)-R_(f) are F and the remaining are H.    -   25. The compound of embodiment 21 or 23 wherein four of        R_(a)-R_(f) are F and the remaining are H.    -   26. The compound of embodiment 21 wherein five of R_(a)-R_(f)        are F and the remaining is H.    -   27. The compound of embodiment 25 wherein R_(a), R_(b), R_(d)        and R_(e) are F and R_(c) and R_(f) are H.    -   28. The compound of embodiment 25 wherein R_(a), R_(c), R_(d)        and R_(f) are F and R_(b) and R_(e) are H.    -   29. The compound of embodiment 25 wherein R_(b), R_(c), R_(e)        and R_(f) are F and R_(a) and R_(d) are H.    -   30. The compound of embodiment 21 wherein all six of R_(a)-R_(f)        are F.    -   31. The compound of any one of embodiments 21-30 wherein the        compound is on free form, such as an anhydrate.    -   32. The compound of any one of embodiments 21-30 wherein the        compound forms a solvate, such as a hydrate.    -   33. The compound of any one of embodiments 21-32 wherein the        compound is on crystalline form, such as a polymorph.    -   34. The compound of any one of embodiments 21 or 25 wherein the        compound of formula I is symmetrical.    -   35. The compound of any one of embodiments 21-34 for use as a        medicine.    -   36. A pharmaceutical composition comprising the compound of any        one of the previous embodiments 1-35 and optionally a        pharmaceutically acceptable additive, such as carrier or        excipient.    -   37. The compound of any one of the embodiments 21-34 for use in        a method for treating a disorder relating to the binding of a        galectin, such as galectin-3 to a ligand in a mammal, such as a        human.    -   38. The compound for use according to embodiment 37, wherein        said disorder is selected from the group consisting of        inflammation; fibrosis, such as pulmonary fibrosis, liver        fibrosis, kidney fibrosis, ophtalmological fibrosis and fibrosis        of the heart; septic shock; cancer; autoimmune diseases;        metabolic disorders; heart disease; heart failure; pathological        angiogenesis, such as ocular angiogenesis or a disease or        condition associated with ocular angiogenesis, e.g.        neovascularization related to cancer; and eye diseases, such as        age-related macular degeneration and corneal neovascularization.    -   39. A method for treatment of a disorder relating to the binding        of a galectin, such as galectin-3, to a ligand in a mammal, such        as a human, wherein a therapeutically effective amount of at        least one compound according to any one of the embodiments 21-28        is administered to a mammal in need of said treatment.    -   40. The method of embodiment 39, wherein said disorder is        selected from the group consisting of inflammation; fibrosis,        such as pulmonary fibrosis, liver fibrosis, kidney fibrosis,        ophtalmological fibrosis and fibrosis of the heart; septic        shock; cancer; autoimmune diseases; metabolic disorders; heart        disease; heart failure; pathological angiogenesis, such as        ocular angiogenesis or a disease or condition associated with        ocular angiogenesis, e.g. neovascularization related to cancer;        and eye diseases, such as age-related macular degeneration and        corneal neovascularization.    -   41. A process of preparing a compound of formula I or a        pharmaceutically acceptable salt or solvate thereof comprising        the steps of a 1,3-dipolar cycloaddition of        1-1′-sulfanediyl-bis[2,4,6-tri-O-acetyl-3-deoxy-3-azido]-β-D-galactopyranoside        with fluoro-substituted phenylacetylenes followed by        deacetylation to yield the compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION

In a broad aspect the present invention relates to a compound of formula(1)

wherein

A is selected from

wherein R₁-R₃ are independently selected from hydrogen (H), fluorine,methyl optionally substituted with a fluorine (F), and OCH₃ optionallysubstituted with a F;R₄ and R₅ are independently selected from H, F, Cl and methyl;R₆ is selected from C₁₋₆ alkyl, branched C₃₋₆ alkyl and C₃₋₇ cycloalkyl;R₇ is selected from aryl, such as phenyl, naphthyl and anthracenyl,optionally substituted with a F, Cl, methyl optionally substituted witha F, and OCH₃ optionally substituted with a F;

B is selected from

wherein R₈-R₁₂ are independently selected from H, F, methyl optionallysubstituted with a fluorine (F), and OCH₃ optionally substituted with aF;R₁₃-R₁₆ are independently selected from H, F, methyl optionallysubstituted with a F, and OCH₃ optionally substituted with a F;R₁₇ is selected from C₁₋₆ alkyl, branched C₃₋₆ alkyl and C₃₋₇cycloalkyl;R₁₈ is selected from aryl, such as phenyl, naphthyl and anthracenyl,optionally substituted with a F, Cl, methyl optionally substituted witha F, and OCH₃ optionally substituted with a F; ora pharmaceutically acceptable salt or solvate thereof.

In an embodiment A and B cannot be identical. It should be understoodthat even though A and B cannot be identical this does not excludecompounds of formula 1 wherein A is 2 and B is 6, A is 3 and B is 7, Ais 4 and B is 8 and A 5 and B is 9, as long as the formulas 2 and 6, 3and 7, 4 and 8, and 5 and 9, do not have the same substituent pattern.

The present inventors have realized that the compound of formula (1)creates a stronger binding affinity to galectin-3. The compounds offormula (1) wherein A is selected from formula 2 and B is selected fromformula 6-9 provides compounds with good solubility, and in particularcompounds of formula 1 wherein A is selected from formula 2 and B isselected from formula 7 have very good affinity to Gal-3 and areselective over Gal-1.

In one embodiment A is selected from formula 2 and B is selected fromany one of formulas 6-9.

In an embodiment A is selected from formula 2 and B is selected fromformula 6, wherein R₁-R₃ are independently selected from H and F, andR₈-R₁₂ are independently selected from H or F.

In a further embodiment A is selected from formula 2 and B is selectedfrom 7, wherein R₁-R₃ are independently selected from H or F, andR₁₃-R₁₄ are both F, and R₁₅-R₁₆ are both H.

In a still further embodiment A is selected from formula 2 and B isselected from 7, wherein R₁ is H, R₂ is H, and R₃ is F, and R₁₃-R₁₄ areboth F, and R₁₅-R₁₆ are both H.

In a further embodiment A is selected from formula 2 and B is selectedfrom 7, wherein R₁-R₃ are all F, and R₁₃-R₁₄ are both F, and R₁₅-R₁₆ areboth H.

In a still further embodiment A is selected from formula 2 and B isselected from 8, wherein R₁-R₃ are independently selected from H or F,and R₁₇ is C₁₋₅ alkyl, such as methyl, n-butyl or tert-butyl.

In a further embodiment A is selected from formula 2 and B is selectedfrom 8, wherein R₁-R₃ are all F, and R₁₇ is methyl.

In a still further embodiment A is selected from formula 2 and B isselected from 8, wherein R₁-R₃ are all F, and R₁₇ is tert-butyl.

In another embodiment A is selected from formula 2 and B is selectedfrom 8, wherein R₁-R₃ are all F, and R₁₇ is n-butyl.

In a further embodiment A is selected from formula 2 and B is selectedfrom 9, wherein R₁-R₃ are independently selected from H or F, and R₁₈ isselected from phenyl optionally substituted with a F, Cl, methyloptionally substituted with a F, and OCH₃ optionally substituted with aF.

In a further embodiment A is selected from formula 2 and B is selectedfrom 9, wherein R₁-R₃ are independently selected from H or F, and R₁₈ isselected from 1-Naphtyl optionally substituted with a F, Cl, methyloptionally substituted with a F, and OCH₃ optionally substituted with aF.

In a further embodiment A is selected from formula 2 and B is selectedfrom 9, wherein R₁-R₃ are independently selected from H or F, and R₁₈ isselected from 2-Naphtyl optionally substituted with a F, Cl, methyloptionally substituted with a F, and OCH₃ optionally substituted with aF.

In a further embodiment A is selected from formula 2 and B is selectedfrom 9, wherein R₁-R₃ are independently selected from H or F, and R₁₈ isselected from anthracenyl optionally substituted with a F, Cl, methyloptionally substituted with a F, and OCH₃ optionally substituted with aF.

In a further embodiment A is selected from formula 2 and B is selectedfrom 9, wherein R₁-R₃ are independently selected from H or F, and R₁₈ isselected from phenyl substituted with four F and one OCH₃, such as2,3,5,6-tetrafluoro-4-methoxy-phenyl; 1-Naphtyl and 2-Naphtyl.

In a still further embodiment A is selected from formula 2 and B isselected from 9, wherein R₁-R₃ are independently selected from H or F,and R₁₈ is selected from 2,3,5,6-tetrafluoro-4-methoxy-phenyl.

In a further embodiment A is selected from formula 2 and B is selectedfrom 9, wherein R₁-R₃ are all F, and R₁₈ is selected from2,3,5,6-tetrafluoro-4-methoxy-phenyl.

In a further embodiment A is selected from formula 2 and B is selectedfrom 9, wherein one of R₁-R₃ is F and the rest is H, and R₁₈ is selectedfrom anthracenyl optionally substituted with a F, Cl, methyl optionallysubstituted with a F, and OCH₃ optionally substituted with a F.

In another embodiment A is selected from formula 3 and B is selectedfrom any one of formulas 6-9.

In another embodiment A is selected from formula 4 and B is selectedfrom any one of formulas 6-9.

In another embodiment A is selected from formula 5 and B is selectedfrom any one of formulas 6-9.

In a further aspect the present invention relates to a compound offormula 1 of the present invention for use as a medicine.

In a still further aspect the present invention relates to apharmaceutical composition comprising a compound of formula 1 of thepresent invention and optionally a pharmaceutically acceptable additive,such as carrier or excipient.

In a further aspect the present invention relates to a compound offormula 1 of the present invention for use in a method for treating adisorder relating to the binding of a galectin, such as galectin-3 to aligand in a mammal, such as a human.

In an embodiment the disorder is selected from the group consisting ofinflammation; fibrosis, e.g. pulmonary fibrosis, or any solid organfibrosis e.g. liver fibrosis, kidney fibrosis, ophtalmological fibrosisand fibrosis of the heart; septic shock; cancer; autoimmune diseases;metabolic disorders; heart disease; heart failure; pathologicalangiogenesis, such as ocular angiogenesis or a disease or conditionassociated with ocular angiogenesis, e.g. neovascularization related tocancer; and eye diseases, such as age-related macular degeneration andcorneal neovascularization.

In a still further aspect the present invention relates to a method fortreatment of a disorder relating to the binding of a galectin, such asgalectin-3, to a ligand in a mammal, such as a human, wherein atherapeutically effective amount of at least one compound of formula 1of the present invention is administered to a mammal in need of saidtreatment.

In an embodiment the disorder is selected from the group consisting ofinflammation; fibrosis, e.g. pulmonary fibrosis, or any solid organfibrosis e.g. liver fibrosis, kidney fibrosis, ophtalmological fibrosisand fibrosis of the heart; septic shock; cancer; autoimmune diseases;metabolic disorders; heart disease; heart failure; pathologicalangiogenesis, such as ocular angiogenesis or a disease or conditionassociated with ocular angiogenesis, e.g. neovascularization related tocancer; and eye diseases, such as age-related macular degeneration andcorneal neovascularization.

In a still further aspect the present invention relates to a process ofpreparing a compound of formula 1 or a pharmaceutically acceptable saltor solvate thereof comprising the steps b1-b4 below:

b1) Reacting a compound X wherein D is selected from propargyloxy andazide with bromine in a solvent, such as DCM, to provide a compound ofthe formula XI;b2) Reacting the compound of the formula XI with a reagent, such asthiourea in acetonitrile followed by release of the thiol using a basesuch as triethylamine to provide a compound of formula XII;alternatively the compound of formula XI is reacted withtriisopropylsilanethiol in an inert solvent, such as acetone, followedby release of the thiol using tetrabutyl ammoniumfluoride to provide acompound of the formula XII;b3a) Reacting the compound of formula XII wherein D is selected fromazide with a compound of formula VIII or a compound of formula XVII

in an inert solvent, such as DMF, using a base, such asdiisopropylamine, catalyzed by CuI to provide the compound of theformula XIII wherein C is selected from formula 2 and 6;b3b) Reacting a compound of formula XII wherein D is selected frompropargyloxy with the corresponding salicylaldehyde in the presence ofp-toluenesulfonylazide and CuI in an inert solvent, such as THF, to givea sulfonimide intermediate, this intermediate is optionally isolatedusing aqueous workup, treatment with a base, such as sodium methoxide inmethanol followed by treatment with dowex to adjust to pH 7 followed byremoval of solvent, and the intermediate is optionally then treated withacetic anhydride using an organic base, such as pyridine to provide acompound of formula XIII wherein D is selected from formula 3 or 7;b3c) Reacting a compound of formula XII wherein D is selected from azidewith methylpropiolate using similar conditions as in step b3a1 to yielda methyl ester, which is reacted with R₆—NH₂ or R₁₇—NH₂ to provide acompound of formula XIII wherein C is selected from formula 4 or 8;b3d) Reacting a compound of the formula XII wherein D is selected fromazide with triphenylphosphine in methanol to provide the correspondingamine, which is reacted with R₇COCl or R₁₈COCl using an organic base,such as pyridine, DMAP in an inert solvent, such as DCM, to provide acompound of the formula XIII wherein C is selected from formula 5 of 9.b4) Reacting the compound of formula XIII wherein C is selected from Aand B with a compound of formula XI wherein D is selected frompropargyloxy and azide using a reagent, such as ammoniumfluoride, in aninert solvent, such as acetonitrile, to provide the compound of formulaXV;b5a) Reacting the compound of formula XV wherein D is selected fromazide with a compound of formula (VIII) or (XVII) in an inert solvent,such as DMF, using a base, such as diisopropylamine, catalyzed by CuI toprovide the compound of the formula (1) wherein A is selected fromformula 2 or B is selected from formula 6;b5b) Reacting a compound of formula XV wherein D is selected frompropargyloxy with the corresponding salicylaldehyde in the prescence ofp-toluenesulfonylazide and CuI in an inert solvent, such as THF, toprovide a sulfonimide intermediate, which is isolated using aqueousworkup, treatment with a base, such as sodium methoxide in methanolfollowed by treatment with dowex to adjust to pH 7 followed by removalof solvent, which intermediate is then treated with acetic anhydrideusing an organic base, such as pyridine, to provide a compound offormula (1) wherein A is defined as 3 or B is selected from formula 7.b5c) Reacting a compound of formula XV wherein D is selected from azidewith methylpropiolate using similar conditions as b5a1 to yield a methylester, which is reacted with R₆—NH₂ or R₁₇—NH₂ to provide a compound offormula 1 wherein A is defined as 4 or B is selected from formula 8.b5d) Reacting a compound of the formula XV wherein D is selected fromazide with triphenylphosphine in methanol to provide the correspondingamine, which amine is then reacted with R₇COCl or R₁₈COCl using anorganic base such as pyridine, DMAP in an inert solvent, such as DCM, toprovide a compound of the formula 1 wherein A is defined as 5 or B isselected from formula 9.

The skilled person will understand that it may be necessary to adjust orchange the order of steps in the process b1-b5, and such change of orderis encompassed by the aspects of the process as described above in thereaction schemes and accompanying description of the process steps.

In a further embodiment the present invention relates to a compound,which is selected from

-   3′-Deoxy-3-O-[(5,6-difluoro-2-oxo-3-chromenyl)methyl]-3′-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,-   3′-Deoxy-3-O-[(5,6-difluoro-2-oxo-3-chromenyl)methyl]-3′-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,-   3′-{4-[(Butylamino)carbonyl]-1H-1,2,3-triazol-1-yl}-3′deoxy-3-O-[(5,6-difluoro-2-oxo-3-chromenyl)methyl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,-   3-{4-[(Butylamino)carbonyl]-1H-1,2,3-triazol-1-yl}-3,3′-dideoxy-3′-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,-   3,3′-Dideoxy-3′-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-(4-methoxy-2,3,5,6-tetrafluoro-benzamido)-1,1′-sulfanediyl-di-β-D-galactopyranoside,-   3-(9-anthracene    carboxamide)-3,3′-Dideoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,-   3-(2-anthracene    carboxamide)-3,3′-Dideoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,-   3,3′-Dideoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-3′-[4-phenyl-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,-   3,3′-dideoxy-3,3′-di-[4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,-   3,3′-bisdeoxy-3,3′-bis-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,    and-   3,3′-bisdeoxy-3,3′-bis-[4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside.

In a more specific embodiment of the compound of formula (1) the presentinvention relates to a compound of formula (I)

wherein R_(a)-R_(f) are independently selected from fluorine orhydrogen, and at least three of R_(a)-R_(f) are F and the remaining areH, or all of R_(a)-R_(f) are F.

The present inventors have realized that having several F substituentsin one or both phenyl groups of the compound of formula (I) creates astronger binding affinity to galectin-3.

In an embodiment at least three of R_(a)-R_(f) are F and the remainingare H.

In another embodiment at least four of R_(a)-R_(f) are F and theremaining are H.

In a further embodiment three of R_(a)-R_(f) are F and the remaining areH. In one embodiment R_(a), R_(b), R_(c) are F and R_(d), R_(e) andR_(f) are H. In a further embodiment R_(a), R_(b), R_(d) are F andR_(c), R_(e) and R_(f) are H. In a still further embodiment R_(a),R_(b), R_(e) are F and R_(c), R_(d) and R_(f) are H. In a furtherembodiment R_(a), R_(b), R_(f) are F and R_(c), R_(d) and R_(e) are H.In a still further embodiment R_(a), R_(c), R_(d) are F and R_(b), R_(e)and R_(f) are H. In a further embodiment R_(a), R_(c), R_(e) are F andR_(b), R_(d) and R_(f) are H. In a still further embodiment R_(a),R_(c), R_(f) are F and R_(b), R_(d) and R_(c) are H. In a furtherembodiment R_(b), R_(c), R_(d) are F and R_(a), R_(e) and R_(f) are H.In a further embodiment R_(b), R_(c), R_(e) are F and R_(a), R_(d) andR_(f) are H. In a still further embodiment R_(b), R_(c), R_(f) are F andR_(a), R_(d) and R_(e) are H. In a further embodiment R_(a), R_(b),R_(d) are H and R_(c), R_(e) and R_(f) are F. In a still furtherembodiment R_(a), R_(b), R_(e) are H and R_(c), R_(d) and R_(f) are F.In a further embodiment R_(a), R_(b), R_(f) are H and R_(c), R_(d) andR_(e) are F. In a still further embodiment R_(a), R_(c), R_(d) are H andR_(b), R_(e) and R_(f) are F. In a further embodiment R_(a), R_(c),R_(e) are H and R_(b), R_(d) and R_(f) are F. In a still furtherembodiment R_(a), R_(c), R_(f) are H and R_(b), R_(d) and R_(e) are F.In a further embodiment R_(b), R_(c), R_(d) are H and R_(a), R_(e) andR_(f) are F. In a further embodiment R_(b), R_(c), R_(e) are H andR_(a), R_(d) and R_(f) are F. In a still further embodiment R_(b),R_(c), R_(f) are H and R_(a), R_(d) and R_(e) are F. In a furtherembodiment R_(a), R_(b), R_(c) are H and R_(d), R_(e) and R_(f) are F.

In a further embodiment four of R_(a)-R_(f) are F and the remaining areH. In one embodiment R_(a), R_(b), R_(c), R_(d), are F and R_(e) andR_(f) are H. In a further embodiment R_(a), R_(b), R_(c), R_(e), are Fand R_(d) and R_(f) are H. In a still further embodiment R_(a), R_(b),R_(c), R_(f), are F and R_(d) and R_(e) are H. In a further embodimentR_(a), R_(d), R_(e), R_(f), are F and R_(b) and R_(c) are H. In a stillfurther embodiment R_(b), R_(d), R_(e), R_(f), are F and R_(a) and R_(c)are H. In a further embodiment R_(c), R_(d), R_(e), R_(f), are F andR_(a) and R_(b) are H. In a still further embodiment R_(a), R_(b),R_(d), R_(e) are F and R_(c) and R_(f) are H. In a further embodimentR_(a), R_(b), R_(d), R_(f) are F and R_(c) and R_(e) are H. In a stillfurther embodiment R_(a), R_(b), R_(e), R_(f) are F and R_(c) and R_(d)are H. In a further embodiment R_(a), R_(c), R_(d), R_(e) are F andR_(b) and R_(f) are H. In a still further embodiment R_(a), R_(c),R_(d), R_(f) are F and R_(b) and R_(e) are H. In a further embodimentR_(a), R_(c), R_(e), R_(f) are F and R_(b) and R_(d) are H. In a stillfurther embodiment R_(b), R_(c), R_(d), R_(e) are F and R_(a) and R_(f)are H. In a further embodiment R_(b), R_(c), R_(d), R_(f) are F andR_(a) and R_(e) are H. In a still further embodiment R_(b), R_(c),R_(e), R_(f) are F and R_(a) and R_(d) are H.

In a further embodiment five of R_(a)-R_(f) are F and the remaining isH. In one embodiment R_(a), R_(b), R_(c), R_(d), R_(e) are F and R_(f)is H. In a further embodiment R_(a), R_(b), R_(c), R_(d), R_(f) are Fand R_(e) is H. In a still further embodiment R_(a), R_(b), R_(c),R_(e), R_(f) are F and R_(d) is H. In a further embodiment R_(a), R_(b),R_(d), R_(e), R_(f) are F and R_(c) is H. In a still further embodimentR_(a), R_(c), R_(d), R_(e), R_(f) are F and R_(b) is H. In a furtherembodiment R_(b), R_(c), R_(d), R_(e), R_(f) are F and R_(a) is H.

In a further embodiment all six of R_(a)-R_(f) are F.

In a still further embodiment the compound of formula I is symmetrical,which means that the two D-galactose groups substituted with a phenylsubstituted triazol attached to the sulphur atom (S) are identical.

In a still further embodiment the compound of formula I is on free form.In one embodiment the free form is an anhydrate. In another embodimentthe free form is a solvate, such as a hydrate.

In a further embodiment the compound of formula I is on crystallineform. The skilled person may carry out tests in order to findpolymorphs, and such polymorphs are intended to be encompassed by theterm “crystalline form” as used herein.

In a further aspect the present invention relates to a compound offormula (I)

wherein R_(a)-R_(f) are independently selected from fluorine orhydrogen, and at least three of R_(a)-R_(f) are F and the remaining areH, or all of R_(a)-R_(f) are F, for use as a medicine.

In a still further aspect the present invention relates to a compound offormula (I)

wherein R_(a)-R_(f) are independently selected from fluorine orhydrogen, and at least three of R_(a)-R_(f) are F and the remaining areH, or all of R_(a)-R_(f) are F, for use in a method for treating adisorder relating to the binding of a galectin, such as galectin-3 to aligand in a mammal, such as a human. In one embodiment the disorder isselected from the group consisting of inflammation; fibrosis, such aspulmonary fibrosis, liver fibrosis, kidney fibrosis, ophtalmologicalfibrosis and fibrosis of the heart; septic shock; cancer; autoimmunediseases; metabolic disorders; heart disease; heart failure;pathological angiogenesis, such as ocular angiogenesis or a disease orcondition associated with ocular angiogenesis, e.g. neovascularizationrelated to cancer; and eye diseases, such as age-related maculardegeneration and corneal neovascularization. In particular the disorderis fibrosis, such as pulmonary fibrosis, liver fibrosis, kidneyfibrosis, ophthalmological fibrosis and fibrosis of the heart.

In a further aspect the present invention relates a method for treatmentof a disorder relating to the binding of a galectin, such as galectin-3,to a ligand in a mammal, such as a human, wherein a therapeuticallyeffective amount of at least one compound of formula (I)

wherein R_(a)-R_(f) are independently selected from fluorine orhydrogen, and at least three of R_(a)-R_(f) are F and the remaining areH, or all of R_(a)-R_(f) are F, is administered to a mammal in need ofsaid treatment. In one embodiment the disorder is selected from thegroup consisting of inflammation; fibrosis, such as pulmonary fibrosis,liver fibrosis, kidney fibrosis, ophtalmological fibrosis and fibrosisof the heart; septic shock; cancer; autoimmune diseases; metabolicdisorders; heart disease; heart failure; pathological angiogenesis, suchas ocular angiogenesis or a disease or condition associated with ocularangiogenesis, e.g. neovascularization related to cancer; and eyediseases, such as age-related macular degeneration and cornealneovascularization.

A process of preparing a compound of formula I or a pharmaceuticallyacceptable salt or solvate thereof comprising the steps of a 1,3-dipolarcycloaddition of1-1′-sulfanediyl-bis[2,4,6-tri-O-acetyl-3-deoxy-3-azido]-β-D-galactopyranoside(A1) with fluoro-substituted phenylacetylenes followed by deacetylationto yield the compound of formula I. In one embodiment deacetylation iscarried out with a mixture of NaOMe and MeOH.

Furthermore the skilled person will understand that the processesdescribed above and herein-after the functional groups of intermediatecompounds may need to be protected by protecting group.

Functional groups that it is desirable to protect include hydroxy, aminoand carboxylic acid. Suitable protecting groups for hydroxy includeoptionally substituted and/or unsaturated alkyl groups (e.g. methyl,allyl, benzyl or tert-butyl), trialkyl silyl or diarylalkylsilyl groups(e.g, t-butyldimethylsilyl, t-butyldipheylsilyl or trimethylsilyl), AcO,TBS, TMS, PMB, and tetrahydropyranyl. Suitable protecting groups forcarboxylic acid include (C1-C6)-alkyl or benzyl esters. Suitableprotecting groups for amino include t-butyloxycarbonyl,benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxy-methyl or2-trimethylsilylethoxycarbonyl (Teoc). Suitable protecting groups for Sinclude S—C(═N)NH₂, TIPS.

The protection and deprotection of functional groups may take placebefore or after any reaction in the above mentioned processes.

Furthermore the skilled person will appreciate that, in order to obtaincompounds of the invention in an alternative, and on some occasions,more convenient, manner, the individual process steps mentionedhereinbefore may be performed in different order, and/or the individualreactions may be performed at a different stage in the overall route(i.e. substituents may be added to and/or chemical transformationsperformed upon, different intermediates to those mentioned hereinbeforein conjunction with a particular reaction). This may negate, or rendernecessary, the need for protecting groups.

In a still further embodiment the compound of formula (1) is on freeform. In one embodiment the free form is an anhydrate. In anotherembodiment the free form is a solvate, such as a hydrate.

In a further embodiment the compound of formula (1) is a crystallineform. The skilled person may carry out tests in order to findpolymorphs, and such polymorphs are intended to be encompassed by theterm “crystalline form” as used herein.

When the compounds and pharmaceutical compositions herein disclosed areused for the above treatment, a therapeutically effective amount of atleast one compound is administered to a mammal in need of saidtreatment.

The term “C₁₋₆ alkyl” as used herein means an alkyl group containing 1-6carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl or hexyl.

The term “branched C₃₋₆ alkyl” as used herein means a branched alkylgroup containing 3-6 carbon atoms, such as isopropyl, isobutyl,tert-butyl, isopentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl,2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl.

The term “C₃₋₇ cycloalkyl” as used herein means a cyclic alkyl groupcontaining 3-7 carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and 1-methylcyclopropyl.

The term “aryl” as used herein means an aromatic carbon group containing6-16 carbon atoms, and no heteroatoms in the ringsystem, including butnot limited to phenyl, naphthyl, anthracenyl.

The term “treatment” and “treating” as used herein means the managementand care of a patient for the purpose of combating a condition, such asa disease or a disorder. The term is intended to include the fullspectrum of treatments for a given condition from which the patient issuffering, such as administration of the active compound to alleviatethe symptoms or complications, to delay the progression of the disease,disorder or condition, to alleviate or relief the symptoms andcomplications, and/or to cure or eliminate the disease, disorder orcondition as well as to prevent the condition, wherein prevention is tobe understood as the management and care of a patient for the purpose ofcombating the disease, condition, or disorder and includes theadministration of the active compounds to prevent the onset of thesymptoms or complications. The treatment may either be performed in anacute or in a chronic way. The patient to be treated is preferably amammal; in particular a human being, but it may also include animals,such as dogs, cats, cows, sheep and pigs.

The term “a therapeutically effective amount” of a compound of formula(1) of the present invention as used herein means an amount sufficientto cure, alleviate or partially arrest the clinical manifestations of agiven disease and its complications. An amount adequate to accomplishthis is defined as “therapeutically effective amount”. Effective amountsfor each purpose will depend on the severity of the disease or injury aswell as the weight and general state of the subject. It will beunderstood that determining an appropriate dosage may be achieved usingroutine experimentation, by constructing a matrix of values and testingdifferent points in the matrix, which is all within the ordinary skillsof a trained physician or veterinary.

In a still further aspect the present invention relates to apharmaceutical composition comprising the compound of formula (1) andoptionally a pharmaceutically acceptable additive, such as a carrier oran excipient.

As used herein “pharmaceutically acceptable additive” is intendedwithout limitation to include carriers, excipients, diluents, adjuvant,colorings, aroma, preservatives etc. that the skilled person wouldconsider using when formulating a compound of the present invention inorder to make a pharmaceutical composition.

The adjuvants, diluents, excipients and/or carriers that may be used inthe composition of the invention must be pharmaceutically acceptable inthe sense of being compatible with the compound of formula (1) and theother ingredients of the pharmaceutical composition, and not deleteriousto the recipient thereof. It is preferred that the compositions shallnot contain any material that may cause an adverse reaction, such as anallergic reaction. The adjuvants, diluents, excipients and carriers thatmay be used in the pharmaceutical composition of the invention are wellknown to a person within the art.

As mentioned above, the compositions and particularly pharmaceuticalcompositions as herein disclosed may, in addition to the compoundsherein disclosed, further comprise at least one pharmaceuticallyacceptable adjuvant, diluent, excipient and/or carrier. In someembodiments, the pharmaceutical compositions comprise from 1 to 99weight % of said at least one pharmaceutically acceptable adjuvant,diluent, excipient and/or carrier and from 1 to 99 weight % of acompound as herein disclosed. The combined amount of the activeingredient and of the pharmaceutically acceptable adjuvant, diluent,excipient and/or carrier may not constitute more than 100% by weight ofthe composition, particularly the pharmaceutical composition.

In some embodiments, only one compound as herein disclosed is used forthe purposes discussed above.

In some embodiments, two or more of the compound as herein disclosed areused in combination for the purposes discussed above.

The composition, particularly pharmaceutical composition comprising acompound set forth herein may be adapted for oral, intravenous, topical,intraperitoneal, nasal, buccal, sublingual, or subcutaneousadministration, or for administration via the respiratory tract in theform of, for example, an aerosol or an air-suspended fine powder.Therefore, the pharmaceutical composition may be in the form of, forexample, tablets, capsules, powders, nanoparticles, crystals, amorphoussubstances, solutions, transdermal patches or suppositories.

Further embodiments of the process are described in the experimentalsection herein, and each individual process as well as each startingmaterial constitutes embodiments that may form part of embodiments.

The above embodiments should be seen as referring to any one of theaspects (such as ‘method for treatment’, ‘pharmaceutical composition’,‘compound for use as a medicament’, or ‘compound for use in a method’)described herein as well as any one of the embodiments described hereinunless it is specified that an embodiment relates to a certain aspect oraspects of the present invention.

All references, including publications, patent applications and patents,cited herein are hereby incorporated by reference to the same extent asif each reference was individually and specifically indicated to beincorporated by reference and was set forth in its entirety herein.

All headings and sub-headings are used herein for convenience only andshould not be construed as limiting the invention in any way.

Any combination of the above-described elements in all possiblevariations thereof is encompassed by the invention unless otherwiseindicated herein or otherwise clearly contradieted by context.

The terms “a” and “an” and “the” and similar referents as used in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context. For instance, when it is stated“optionally substituted with a” it means “optionally substituted withone or more”.

Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless other-wise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein. Unless otherwise stated, all exact valuesprovided herein are representative of corresponding approximate values(e.g., all exact exemplary values provided with respect to a particularfactor or measurement can be considered to also pro-vide a correspondingapproximate measurement, modified by “about,” where appropriate).

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext.

The use of any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise indicated. No language in the specification should beconstrued as indicating any element is essential to the practice of theinvention unless as much is explicitly stated.

The citation and incorporation of patent documents herein is done forconvenience only and does not reflect any view of the validity,patentability and/or enforceability of such patent documents.

The description herein of any aspect or embodiment of the inventionusing terms such as “comprising”, “having”, “including” or “containing”with reference to an element or elements is intended to provide supportfor a similar aspect or embodiment of the invention that “consists of”,“consists essentially of”, or “substantially comprises” that particularelement or elements, unless otherwise stated or clearly contradicted bycontext (e.g., a composition described herein as comprising a particularelement should be understood as also describing a composition consistingof that element, unless otherwise stated or clearly contradicted bycontext).

This invention includes all modifications and equivalents of the subjectmatter recited in the aspects or claims presented herein to the maximumextent permitted by applicable law.

The present invention is further illustrated by the following examplesthat, however, are not to be construed as limiting the scope ofprotection. The features disclosed in the foregoing description and inthe following examples may, both separately and in any combinationthereof, be material for realizing the invention in diverse formsthereof.

Experimental Section 1 Evaluation of Kd Values

The affinity of compounds S8a-c, S11, S16, S20a-b and S21 for galectinswere determined by a fluorescence anisotropy assay where the compoundwas used as an inhibitor of the interaction between galectin and afluorescein tagged saccharide probe as described Sörme, P.,Kahl-Knutsson, B., Huflejt, M., Nilsson, U. J., and Leffler H. (2004)Fluorescence polarization as an analytical tool to evaluategalectin-ligand interactions. Anal. Biochem. 334: 36-47, (Sörme et al.,2004) and Monovalent interactions of Galectin-1 By Salomonsson, Emma;Larumbe, Amaia; Tejler, Johan; Tullberg, Erik; Rydberg, Hanna; Sundin,Anders; Khabut, Areej; Frejd, Torbjorn; Lobsanov, Yuri D.; Rini, JamesM.; et al, From Biochemistry (2010), 49(44), 9518-9532, (Salomonsson etal., 2010). The assay was adapted to be able to measure the highaffinity of the present compound for galectin-3 by using a probe (SY)constructed to have high affinity for galectin-3 based on the structureof3,3′-Dideoxy-3,3′-di-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,which made it possible to use a low concentration of galectin-3 (50 nM).100 nM albumin was included as a carrier to prevent protein loss at suchlow concentration of galectin.

Compounds of the type S8a-c were found to be less active towardsgalectin-1 as compared to3,3′-Dideoxy-3,3′-di-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(structure below) and as a consequence therefore more selective towardsGalectin-3.

Kd values for compounds 8a-c, S11, S16, S20a-b and S21 and referencecompound3,3′-Dideoxy-3,3′-di-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(SX)

Galectin-1 Galectin-3 Example Kd (μM) Kd (μM) S8a 0.32 0.028 S8b 0.480.002 S8c 1.2 0.072 S11 0.077 0.001 S16 0.09 0.007 S20a 0.38 0.064 S20b0.49 0.14 S21 0.066 0.003 SX 0.060 0.001

SYNTHESIS OF EXAMPLES Materials and Methods

NMR spectra were recorded on a Bruker Avance II 400 MHz spectrometer atambient temperature. ¹H-NMR spectra were assigned using 2D-methods(COSY). Chemical shifts are given in ppm downfield from the signal forMe₄Si, with reference to residual CHCl₃ or CD₂HOD. HRMS was determinedby direct infusion on a Waters XEVO-G2 QTOF mass spectrometer usingelectrospray ionization (ESI). Reactions were monitored by TLC usingaluminum-backed silica gel plates (Merck 60F₂₅₄) and visualized using UVlight and by charring with ethanolic H₂SO₄ (7%). Column chromatographywas performed using silica gel (40-60 μm, 60 Å) columns. Solvents weredried by storing over activated M.S. Reagents were supplied bySigma-Aldrich and used as it is.

Examples 1-3

Example 1 S8a)3′-Deoxy-3-O-[(5,6-difluoro-2-oxo-3-chromenyl)methyl]-3′-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside

To a solution of S7 (90 mg, 0.16 mmol) and CuI (3 mg, 0.016 mmol) in DMF(8 mL) was 1-ethynyl-3-fluorobenzene (0.036 mL, 0.31 mmol) addedfollowed by diisopropylethylamine (0.027 mL, 0.16 mmol). The resultingsuspension was stirred at rt for 6 h followed by 90 min at 50° C. to getfull conversion of starting material. The solution was evaporated onsilica gel and purified with flash chromatography (CH₂Cl₂:MeOH19:1->14:1) to give S8a (48 mg, 44%). ¹H-NMR (MeOD, 400 MHz) δ 8.52 (s,1H), 8.39 (s, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.60 (d, J=10.0 Hz, 1H),7.53-7.42 (m, 2H), 7.20 (d, J=9.4 Hz, 1H), 7.07 (td, J=8.4, 2.3 Hz, 1H),4.95 (d, J=9.6 Hz, 1H), 4.88 (dd, J=10.7, 3.0 Hz, 1H), 4.77 (d, J=9.9Hz, 1H), 4.73 (dd, J=15.4, 1.5 Hz, 1H), 4.63 (dd, J=15.4, 1.5 Hz, 1H),4.43 (t, J=10.4 Hz, 1H), 4.22 (d, J=2.7 Hz, 1H), 4.13 (d, J=2.7 Hz, 1H),3.97 (t, J=9.6 Hz, 1H), 3.87-3.79 (m, 3H), 3.75-3.63 (m, 3H), 3.53 (dd,J=9.2, 3.1 Hz, 1H).

HRMS calcd for [C₃₀H₃₀F₃N₃O₁₁NaS]⁺, 720.1451; found: 720.1443.

Example 2 S8b)3′-Deoxy-3-O-[(5,6-difluoro-2-oxo-3-chromenyl)methyl]-3′-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside

To a solution of S7 (26 mg, 0.045 mmol) and CuI (1 mg, 0.0045 mmol) inDMF (4 mL) was added 3,4,5-trifluorophenylacetylene (0.009 mL, 0.090mmol) followed by diisopropylethylamine (0.008 mL, 0.045 mmol). Theresulting suspension was stirred at 50° C. for 3 h. The solution wasevaporated on silica gel and purified with flash chromatography(CH₂Cl₂:MeOH 19:1->14:1) to give S8b (15 mg, 45%).

¹H-NMR (MeOD, 400 MHz) δ 8.55 (s, 1H), 8.38 (s, 1H), 7.63 (dd, J=8.9,6.6 Hz, 2H), 7.50 (q, J=9.1 Hz, 1H), 7.20 (d, J=9.2 Hz, 1H), 4.94 (d,J=9.6 Hz, 1H), 4.88 (dd, J=9.8, 3.0 Hz, 1H), 4.77 (d, J=9.9 Hz, 1H),4.73 (dd, J=15.4, 1.5 Hz, 1H), 4.63 (dd, J=15.4, 1.5 Hz, 1H), 4.40 (t,J=9.6 Hz, 1H), 4.22 (d, J=2.7 Hz, 1H), 4.12 (d, J=2.8 Hz, 1H), 3.96 (t,J=9.6 Hz, 1H), 3.86-3.79 (m, 3H), 3.75-3.67 (m, 2H), 3.64 (m, 1H), 3.53(dd, J=9.2, 3.1 Hz, 1H).

HRMS calcd for [C₃₀H₂₉F₅N₃O₁₁S]⁺, 734.1443; found: 734.1453.

Example 3 S8c)3′-{4-[(Butylamino)carbonyl]-1H-1,2,3-triazol-1-yl}-3′deoxy-3-O-[(5,6-difluoro-2-oxo-3-chromenyl)methyl]-1,1′-sulfanediyl-di-β-D-galactopyranoside

Compound S7 (60 mg, 0.104 mmol) was dissolved in acetic anhydride (3 mL)and pyridine (3 mL), stirred at rt o.n. The volatiles were evaporatedand the obtained residue followed by addition of CuI (4.9 mg, 0.026mmol) and acetonitrile (4 mL). Methyl propiolate (0.014 mL, 0.156 mmol)was added followed by diisopropylethylamine (0.018 mL, 0.104 mmol) andthe mixture was stirred at 50° C. for 4 h. The solvent was evaporatedand obtained residue was stirred with a solution of butylamine 20% inMeOH for 6 days at rt. The solution was evaporated and the residue waspurified with flash chromatography (CH₂Cl₂:MeOH 19:1->9:1) to give S8c(0.3 mg, 0.4%).

HRMS calcd for [C₂₉H₃₇F₂N₄O₁₂S]⁺, 703.2090; found: 703.2097.

Preparation of Starting Materials Examples 1-3 S2) 4-Methoxyphenyl2,4,6-tri-O-acetyl-3-O-propargyl-β-D-galactopyranoside

Compound S1 (1.45 g, 4.48 mmol) (L. Zhang, G. Wei, Y. Du, Carbohydr.Res., 2009, 344, 2083-2087) was dissolved in acetic anhydride (10 mL)and pyridine (10 mL) and stirred at rt (room temperature) o.n. (overnight) The solvent was evaporated to give S2 (2.01 g, 99%) as a whitesolid.

¹H-NMR (CDCl₃, 400 MHz) δ 6.96 (d, J=9.1 Hz, 2H), 6.81 (d, J=9.1 Hz,2H), 5.44 (d, J=2.5 Hz, 1H), 5.31 (dd, J=10.0, 8.0 Hz, 1H), 4.91 (d,J=8.0 Hz, 1H), 4.20 (m, 2H), 3.95 (t, J=6.5 Hz, 1H,), 3.90 (dd, J=10.0,3.5 Hz, 1H), 3.77 (s, 3H), 2.17 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H).

HRMS calcd for [C₂₂H₂₆O₁₀Na]⁺, 473.1424; found: 473.1426.

S3) 4-Methoxyphenyl2,4,6-tri-O-acetyl-3-O-[(5,6-difluoro-2-oxo-3-cromenyl)methyl]-β-D-galactopyranoside

To a mixture of S2 (1.23 g, 2.72 mmol), 5,6-difluorosalicylaldehyde (860mg, 5.44 mmol) and CuI (518 mg, 2.72 mmol) in THF (100 mL) wasp-toluenesulfonyl azide (1.34 g, 6.80 mmol) dissolved in THF (5 mL)added. The resulting mixture was stirred for 30 min before triethylamine(1.51 mL, 10.88 mmol) was added and the resulting solution was stirredfor 1 h at rt. After evaporation of the solvent was the residue dilutedwith CH₂Cl₂ and washed with sat. aq. NH₄Cl and brine. The organic phasewas dried and evaporated, after which the obtained residue was dissolvedin MeOH (75 mL) and NaOMe (1 M, 25 mL). The resulting solution wasstirred o.n. followed by addition of Dowex to adjust pH to 7 and thesolution was concentrated. The obtained residue was dissolved in aceticanhydride (10 mL) and pyridine (10 mL) and stirred at rt for 5 h.Evaporation of the solvents and purification by column chromatography(heptane:EtOAc 3:1->1:1) gave S3 (1.35 g, 82%).

¹H-NMR (CDCl₃, 400 MHz) δ 7.91 (s, 1H), 7.33 (q, J=9.4 Hz, 1H), 7.09 (d,J=9.3 Hz, 1H), 6.96 (d, J=9.1 Hz, 2H), 6.82 (d, J=9.1 Hz, 2H), 5.57 (d,J=2.5 Hz, 1H), 5.45 (dd, J=10.0, 7.9 Hz, 1H), 4.90 (d, J=8.0 Hz, 1H),4.67 (dd, J=14.5, 1.5 Hz, 1H), 4.48 (dd, J=14.5, 1.5 Hz, 1H), 4.28-4.18(m, 2H), 3.97 (t, J=6.4 Hz, 1H), 3.78 (s, 3H), 3.76 (dd, J=10.1, 3.4 Hz,1H), 2.20 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H).

S4) Triisopropylsilyl2,4,6-tri-O-acetyl-3-O-[(5,6-difluoro-2-oxo-3-cromenyl)methyl]-1-thio-β-D-galactopyranoside

Zinc bromide (25 mg, 0.11 mmol) and S3 (1.35 g, 2.23 mmol) weredissolved in CH₂Cl₂ (50 mL) and acetyl bromide (0.49 mL, 6.68 mmol) wasadded, the solution was stirred for 14 h at rt. The solution was dilutedwith CH₂Cl₂ and washed three times with sat. aq. NaHCO₃ and three timeswith brine. The organic phase was dried and evaporated. The obtainedresidue and K₂CO₃ (769 mg, 5.57 mmol) were dissolved in acetone (40 mL)and triisopropylsilanethiol (0.60 mL, 2.78 mmol) was added. The solutionwas stirred 18 h at rt followed by evaporation of the solvent, CH₂Cl₂was added and it was washed with water. The organic phase was dried,evaporated and the residue purified with flash chromatography(heptane:EtOAc 4:1->1:1) to obtain S4 (566 mg, 38%).

¹H-NMR (CDCl₃, 400 MHz) δ 7.88 (s, 1H), 7.32 (q, J=9.4 Hz, 1H), 7.08 (d,J=7.3 Hz, 1H), 5.55 (d, J=2.5 Hz, 1H), 5.25 (t, J=9.7 Hz, 1H), 4.63 (m,2H, H−1), 4.43 (dd, J=14.5, 1.5 Hz, 1H), 4.14 (m, 2H), 3.82 (t, J=6.3Hz, 1H), 3.65 (dd, J=9.7, 3.4 Hz, 1H), 2.17 (s, 3H), 2.10 (s, 3H), 2.06(s, 3H), 1.27 (m, 3H), 1.13 (d, J=6.4 Hz, 18H).

S6)2,4,6-Tri-O-acetyl-3-O-[(5,6-Difluoro-2-oxo-3-chromenyl)methyl]-2′,4′,6′-tri-O-acetyl-3′-azido-3′-deoxy-1,1′-sulfanediyl-di-β-D-galactopyranoside

Compounds S4 (537 mg, 0.80 mmol) and S5 (370 mg, 0.94 mmol) (T. L.Lowary, O. Hindsgaul, Carbohydr. Res., 1994, 251, 33-67) were dissolvedin acetonitrile (30 mL) and nitrogen gas was bubbled through thesolution for 10 min after which tetrabutylammonium fluoride (0.84 mL, 1M in THF, 0.84 mmol) was added. After 2.5 h was the solvent removed, theresidue was dissolved in CH₂Cl₂ and washed with water. The organic phasewas dried, evaporated and purified with flash chromatography(heptane:EtOAc 3:1->1:2) to give S6 (652 mg, 98%).

¹H-NMR (CDCl₃, 400 MHz) δ 7.86 (s, 1H), 7.33 (q, J=9.3 Hz, 1H), 7.09 (m,1H), 5.58 (d, J=3.1 Hz, 1H), 5.48 (d, J=2.9 Hz, 1H), 5.21 (t, J=10.1 Hz,1H), 5.19 (t, J=10.2 Hz, 1H), 4.81 (d, J=10.0 Hz, 1H), 4.79 (d, J=10.0Hz, 1H), 4.64 (dd, J=14.5, 1.5 Hz, 1H), 4.46 (dd, J=14.3, 1.3 Hz, 1H),4.23-4.11 (m, 4H), 3.86 (t, J=6.3 Hz, 2H), 3.73 (dd, J=9.6, 3.4 Hz, 1H),3.66 (dd, J=10.1, 3.4 Hz, 1H), 2.18 (s, 6H), 2.14 (s, 3H), 2.09 (s, 3H),2.08 (s, 3H), 2.07 (s, 3H).

S7)3′-Azido-3′-deoxy-3-O-[(5,6-Difluoro-2-oxo-3-chromenyl)methyl]-1,1′-sulfanediyl-di-β-D-galactopyranoside

NaOMe (1 M, 10 mL) was added to a stirred solution of S6 (525 mg, 0.63mmol) in MeOH (15 mL) and CH₂Cl₂ (2 mL). After stirring o.n. the pH wasadjusted to 7 by Dowex and concentrated. The residue was purified bycolumn chromatography (CH₂Cl₂:MeOH 19:1->9:1) to give S7 (195 mg, 53%).

HRMS calcd for [C₂₂H₂₅F₂N₃O₁₁NaS]⁺, 600.1076; found: 600.1079.

Example 4

S11)3-{4-[(Butylamino)carbonyl]-1H-1,2,3-triazol-1-yl}-3,3′-dideoxy-3′-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside

To a solution of S10 (26 mg, 0.032 mmol) and CuI (0.6 mg, 0.003 mmol) inDMF (3 mL) was methyl propiolate (0.004 mL, 0.048 mmol) added followedby diisopropylethylamine (0.005 mL, 0.032 mmol) and the mixture wasstirred at 50° C. for 54 h. The reaction was quenched with sat. aq.NH₄Cl followed by evaporation of the solvent was evaporated and waterwas added. The mixture was extracted twice with CH₂Cl₂ and the organicphases were washed with brine, dried and evaporated. The obtainedresidue was stirred with a solution of butylamine 20% in MeOH for 3 daysat rt. The solution was evaporated and the residue was purified withflash chromatography (CH₂Cl₂:MeOH 9:1) to give S11 (13.2 mg, 60%)

¹H-NMR (MeOD, 400 MHz) δ 8.59 (s, 1H), 8.55 (s, 1H), 7.43 (dd, J=8.8,6.5 Hz, 2H,), 4.93 (dd, J=10.4, 2.9 Hz, 2H), 4.86 (d, J=9.5 Hz, 2H),4.76 (m, 2H), 4.14 (d, J=2.7 Hz, 1H), 4.12 (d, J=2.7 Hz, 1H), 3.89-3.78(m, 4H), 3.71 (m, 1H), 3.68 (m, 1H), 3.39 (t, J=7.0 Hz, 2H), 1.60 (m,2H), 1.40 (m, 2H), 0.96 (t, J=7.3 Hz, 3H).

HRMS calcd for [C₂₇H₃₄F₃N₇O₉SNa]⁺, 712.1980; found: 712.1989.

Preparation of Starting Material for Example 4 S10)2,2′,4,4′,6,6′-Hexa-O-acetyl-3′-azido-3-3′-dideoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside

To a solution of S9 (300 mg, 0.454 mmol) and CuI (8.6 mg, 0.045 mmol) inDMF (10 mL) was 3,4,5-trifluorophenylacetylene (0.042 mL, 0.409 mmol)added followed by diisopropylethylamine (0.079 mL, 0.454 mmol). Theresulting suspension was stirred at rt for 1 h after which the reactionwas quenched with sat. aq. NH₄Cl followed by evaporation of the solventwas evaporated and water was added. The mixture was extracted twice withCH₂Cl₂ and the organic phases were washed with brine, dried andevaporated. The obtained residue was purified with flash chromatography(heptane:EtOAc 1:1) to give S10 (90 mg, 24%).

¹H-NMR (CDCl₃, 400 MHz) δ 7.82 (s, 1H), 7.43 (t, J=8.0 Hz, 2H), 5.73 (t,J=10.4 Hz, 1H), 5.61 (d, J=2.7 Hz, 1H), 5.50 (d, J=2.5 Hz, 1H), 5.23 (t,J=10.0 Hz, 1H), 5.16 (dd, J=11.0, 3.2 Hz, 1H), 4.95 (d, J=9.7 Hz, 1H),4.82 (d, J=10.0 Hz, 1H), 4.26-4.07 (m, 5H), 3.91 (t, J=6.4 Hz, 1H), 3.67(dd, J=10.1, 3.3 Hz, 1H), 2.19 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H), 2.08(s, 3H), 2.06 (s, 3H), 1.92 (s, 3H).

HRMS calcd for [C₃₂H₃₅F₃N₆O₁₄SNa]⁺, 839.1782; found: 839.1771.

Example 5

S16)3,3′-Dideoxy-3′-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-(4-methoxy-2,3,5,6-tetrafluoro-benzamido)-1′-sulfanediyl-di-β-D-galactopyranoside

S14 (22.5 mg, 0.036 mmol) and S15 (18.2 mg, 0.036 mmol) was dissolved inacetonitrile (10 ml) followed by addition of TBAF (11 μl, 1M). Thereaction was stirred under nitrogen atmosphere for 1 hour followed byevaporation of the solvents. The crude material was dissolved in MeOH(10 ml) followed by addition of NaOMe (500 μl, 1M). The reaction mixturewas stirred o.n. followed by adjustment of pH to neutral (pH7) usingDuolit IR120, filtered, evaporation. The crude material was purified byflash chromatography (DCM/MeOH (8:1)) to give crude material. Thismaterial (12 mg, 0.020 mmol) was dissolved in

DMF (8 ml) followed by addition of 1-ethynyl-3-fluorobensen (7 μl, 0.061mmol), CuI (0.4 mg, 0.002 mmol) and triethylamine (2.8 μl, 0.020 mmol).The reaction was stirred under nitrogen atmosphere for 48 hour andfollowed by evaporation of the solvents. The crude material was purifiedby flash chromatography (DCM/MeOH (7:1)) to give the title compound S16(6.2 mg, 24%).

¹H NMR (400 MHz, CD₃OD) δ 8.49 (s, 1H), 7.79-7.50 (m, 2H), 7.46 (td,J=8.0, 6.0 Hz, 1H), 7.08 (ddd, J=8.3, 2.6, 1.3 Hz, 1H), 5.26-4.76 (m,3H), 4.52-4.28 (m, 1H), 4.18 (dd, J=10.4, 3.0 Hz, 1H), 4.12 (dd, J=3.7,2.2 Hz, 4H), 4.04 (d, J=2.9 Hz, 1H), 3.90-3.64 (m, 7H).

ESIMS m/z calcd for [C₂₈H₃₀F₅N4O₁₀S]⁺, 709.1603; found 709.1609.

Preparation of Starting Materials for Example 5 S13)1,2,4,6-Tetra-O-acetyl-3-deoxy-3-(4-methoxy-2,3,5,6-tetrafluoro-benzamido)-β-D-galactopyranose

Compound 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-D-galactopyranose S12(1600 mg, 4.286 mmol) was dissolved in ethanol (90 ml) and cyclohexene(180 ml). Palladium hydroxide (200 mg, 1.424 mmol) was added and thereaction was heated to reflux at 90° C. for 20 min. The reaction mixturewas filtered, concentrated and dissolved in DCM (200 ml) and pyridine(1040 μl, 12.858 mmol) and 4-methoxy-2,3,5,6-tetrafluoro-benzoylchloride(1247 mg, 5.143 mmol) was added. The reaction was stirred for four hoursunder nitrogen atmosphere and then washed with NaHCO₃ (2*150 ml) anddried with MgSO₄. The residue was purified by flash chromatography(Heptane/EtOAc: 1:1) to give S13 (934 mg) in 40% yield.

¹H NMR (400 MHz, CDCl₃) δ 6.26 (d, J=7.3 Hz, 1H), 5.81 (dd, J=8.2, 3.1Hz, 1H), 5.64-5.41 (m, 1H), 5.16 (ddd, J=11.2, 8.2, 3.0 Hz, 1H), 4.54(td, J=7.8, 4.5 Hz, 1H), 4.23-3.96 (m, 6H), 2.28-1.93 (m, 12H).

ESIMS m/z calcd for [C₂₂H₂₃F₄NO₁₁Na]⁺, 576.1105; found 576.1104.

S14)2,4,6-Tri-O-acetyl-3-(4-methoxy-2,3,5,6-tetrafluoro-benzamido)-α-D-galactopyranosylbromide

S13 (21.9 mg, 0.0395 mmol) was dissolved in DCM (4 ml) and Ac₂O (10.1μl, 0.11 mmol) was added. The reaction mixture was stirred undernitrogen atmosphere and cooled to 0° C. HBr/AcOH (88 μl, 0.043 mmol) wasadded and the reaction was stirred for 2 hours, washed with NaHCO₃ (1*50ml), brine (1*50 ml), dried over MgSO₄, filtered and concentrated togive S14 (20.1 mg) in 89% yield. ¹H NMR (400 MHz, CDCl₃) δ 6.59 (d,J=3.8 Hz, 1H), 6.12 (d, J=7.9 Hz, 1H), 5.66 (dd, J=3.1, 1.1 Hz, 1H),5.13 (dd, J=11.3, 3.8 Hz, 1H), 4.93 (ddd, J=11.2, 8.0, 3.1 Hz, 1H), 4.55(t, J=6.4 Hz, 1H), 4.19 (dd, J=11.6, 6.0 Hz, 1H), 4.13 (t, J=1.7 Hz,3H), 4.06 (dd, J=11.6, 6.9 Hz, 1H), 2.16 (s, 3H), 2.14 (s, 3H), 2.07 (s,3H).

Examples 6 and 7

Example 6 S20a) 3-(9-anthracenecarboxamide)-3,3′-Dideoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside

The amine compound S19 (37 mg, 0.07 mmol) was suspended in dry THFfollowed by addition of 9-Anthracene carbonyl chloride (35 mg, 0.14mmol). The reaction mixture was stirred at room temperature under N₂atmosphere. Et₃N (0.1 mL) was added. After 2h 9-Anthracene carbonylchloride (35 mg, 0.14 mmol) was added. The reaction was followed by TLCin 6:1 CH₂Cl₂:MeOH. After the reaction was complete, the solvents wereevaporated and the residue was purified by flash chromatography usingDCM:MeOH as eluent to afford pure compound 5 in 46% yield.

¹H NMR (CD₃OD, 400 MHz) δ: 8.58 (s, 1H), 8.50 (s, 1H), 8.39 (d, 9.2 Hz,1H), 8.17 (d, 8.4 Hz, 1H), 8.08 (m, 2H), 7.66 (m, 7H), 7.10 (t, 1H),4.94 (2H obscured under H₂O), 4.57 (m, 2H), 4.29 (d, 1H, 2.8 Hz), 4.12(d, 1H, 2.4 Hz), 3.99 (t, 1H, 10.0 Hz), 3.87 (m, 7H).

¹³C NMR (CD₃OD, 100 MHz) δ: 172.36, 165.88, 163.45, 134.36, 134.27,133.26, 132.62, 131.93, 131.85, 129.53, 129.39, 129.16, 127.64, 126.96,126.62, 126.34, 122.43, 115.88, 115.67, 113.31, 113.08, 86.85 (C-1),86.53 (C-1′), 81.87, 81.44, 69.80, 69.74, 69.67, 68.98, 68.50, 63.03,62.70, 58.47, 40.42.

HRMS m/z calcd. For C₃₅H₃₅N₄O₉FNaS (M+Na⁺) 729.2000, found 729.2006.

Example 7 S20b) 3-(2-anthracenecarboxamide)-3,3′-Dideoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside

The amine compound 4 (20 mg, 0.039 mmol) was suspended in dry THFfollowed by addition of 2-Anthracene carbonyl chloride (19.1 mg, 0.0796mmol). The reaction mixture was stirred at room temperature under N₂atmosphere. Et₃N (0.1 mL) was added. After 2h 2-Anthracene carbonylchloride (19.1 mg, 0.0796 mmol) was added. The reaction was followed byTLC in 6:1 CH₂Cl₂:MeOH. After the reaction was complete, the solventswere evaporated and the residue was purified by flash chromatographyusing DCM:MeOH as eluent to afford pure compound 6 in 44% yield.

¹H NMR (CD₃OD, 400 MHz) δ: 8.66 (s, 1H, ArH), 8.62 (s, 1H, ArH), 8.53(s, 2H, triazole-H, ArH), 8.13 (m, 3H, ArH), 7.92 (dd, 1.6 Hz and 1.6Hz, 1H, ArH), 7.68 (m, 5H, ArH), 7.10 (m, 1H, ArH), 4.96 (3H obscuredunder H₂O, H-1, H-1′, H-3), 4.53 (t, 10.4 Hz and 10.0 Hz, 1H, H-3), 4.29(dd, 1H, H-3′), 4.16 (m, 3H, H-4, H-4′, H-2′), 3.90 (m, 6H, H-5, H-5′,H-6, H-6′).

¹³C NMR (CD₃OD, 100 MHz) δ: 134.32, 133.67, 132.53, 131.92, 129.88,129.65, 129.36, 129.26, 129.07, 127.43, 127.25, 127.00, 124.37, 122.46,113.31, 86.46, 86.43, 81.75, 81.44, 69.82, 69.43, 69.31, 69.01, 68.50,63.06, 62.63, 58.95.

HRMS m/z calcd. For C₃₅H₃₅N₄O₉FNaS (M+Na⁺) 729.2000, found (M+Na)729.2006.

Preparation of Starting Materials Examples 6 and 7 S17)2,2′,4,4′,6,6′-Hexa-O-acetyl-3′-azido-3-3′-dideoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside

A solution of2,2′,4,4′,6,6′-Hexa-O-acetyl-3,3′-diazido-3,3′-dideoxy-1,1′-sulfanediyl-di-β-D-galactoside(S9) (1.06 g, 1.60 mmol), 3-fluorophenyl acetylene (0.16 mL, 1.44 mmol),CuI (15.2 mg, 0.08 mmol) in dry CH₃CN (20 mL) in a 100 mL round bottomedflask was stirred under nitrogen for 15 mins. Et₃N (0.11 mL, 0.8 mmol)was added slowly via a syringe. The reaction mixture was stirred at roomtemperature for 1h to afford monocycloaddition product, monitoringproduct formation using TLC 1:2, n-heptane-EtOAc. Solvents wereevaporated in vacuo and the residue was dissolved in CH₂Cl₂ (40 mL) andwashed successively with aqueous NH₄Cl (20 mL) and brine (20 mL). Theorganic layer was separated, dried over Na₂SO₄ and the solvents wereevaporated in vacuo. The residue was purified by flash chromatographyusing n-heptane-EtOAc as eluent to afford monotriazole S17 in 42% yield.

¹H NMR (CDCl₃, 400 MHz) δ: 7.83 (s, 1H), 7.54 (t, 2H, 7.6 Hz and 8.8Hz), 7.38 (m, 1H), 7.03 (m, 1H), 5.73 (t, 1H, 10.4 Hz), 5.62 (d, 1H, 2.4Hz), 5.50 (d, 1H, 2.4 Hz), 5.24 (m, 2H), 4.98 (d, 1H, 9.6 Hz), 4.85 (d,1H, 10.0 Hz), 4.21 (m, 5H), 3.92 (m, 1H), 3.69 (dd, 1H, 10.4 Hz and 2.8Hz).

S18)3′-Azido-3,3′-dideoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside

The above monotriazole S17 (525 mg, 0.67 mmol) was treated with 0.5MNaOMe in MeOH until complete conversion monitored by TLC. The reactionmixture was neutralized using DOWEX H⁺ resin. The resin was filtered offand the solvents where evaporated. The crude material was purified byflash chromatography using CH₂Cl₂:MeOH as eluent. This afforded compoundS18 in 96% yield. ¹H NMR (CD₃OD, 400 MHz) δ: 8.51 (s, 1H), 7.67 (dd,1H), 7.61 (m, 1H), 7.46 (m, 1H), 7.07 (m, 1H), 4.93 (2H obscured underH₂O), 4.78 (d, 1H, 10.0 Hz), 4.48 (t, 1H, 10.0 Hz), 4.13 (d, 1H, 3.2Hz), 4.04 (d, 1H, 9.6 Hz and 10.0 Hz), 3.97 (d, 1H, 2.4 Hz) 3.85 (m,6H), 3.40 (dd, 1H, 9.6 Hz and 2.8 Hz 1H).

S19)3′-Amino-3,3′-dideoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside

A solution of S18 (300 mg, 0.567 mmol) in MeOH (0.7 mL) and Pd/C (10%,10 mg) was hydrogenated under a hydrogen atmosphere for 3h at roomtemperature. The reaction was monitored by mass spectrometry. After thecompletion the reaction mixture was filtered through celite and thesolvents were evaporated to give S19 in 86% yield. The material was usedin the next step without further purification.

Example 8

S21)3,3′-Dideoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-3′-[4-phenyl-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside

S10 (50 mg), phenylacetylene (20 μl) and CuI (3 mg) were mixed and takenup in in acetonitrile (10 ml). The reaction mixture was degassed (argon)followed by addition of Hünig's base (50 μl). The reaction mixture wasstirred at rt over night. The solvents were removed in vacuo followed bypurification using flash chromatography (SiO2/heptane:ethyl acetate95:5=>5:95). The appropriate fractions were combined and the solventswere removed in vacuo and the residue was dissolved in methanol (10 ml).1M sodium methoxide in methanol (1.5 ml) was added and the reactionmixture was stirred for 2 h. TFA (0.2 ml) was added and the solventswere removed in vacuo. The residue was purified by HPLC(C18/MeCN:H₂O:0.1% TFA). Freezedrying afforded the title compound as awhite solid (8 mg).

¹H NMR (400 MHz, Methanol-d₄) δ 8.59 (s, 1H), 8.52 (s, 1H), 7.82 (d,J=7.7 Hz, 2H), 7.65-7.56 (m, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.33 (t, J=7.4Hz, 1H), 4.85 (m, 6H), 4.16 (d, J=8.7 Hz, 2H), 3.91-3.78 (m, 4H), 3.72(dd, J=11.2, 4.1 Hz, 2H).

ESI-MS m/z calcd for [C₂₈H₃₀F₃N₆O₈S]⁺ (M+H)⁺: 667.17; found: 667.1.

Preparation of Starting Material for Example 8 S10)3′-Azido-3,3′-dideoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside

3,3′-Diazido-3,3′-dideoxy-1,1′-sulfanediyl-di-β-D-galactopyranoside S9(131 mg) and trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (45 μl)were dissolved in acetonitrile (5 ml), the reaction mixture was degassed(argon). Cesium fluoride (30 mg) was added and the reaction mixture wasstirred for 5 min. CuI (4 mg) was added, followed by Hünig's base (100μl). The mixture was stirred at rt over night followed by removal ofsolvents in vacuo. The residue was evaporated on to silica and purifiedby flash chromatography (SiO2/heptane:ethyl acetate 95:5=>5:95). Theappropriate fractions were concentrated in vacuo and the residuedissolved in methanol (10 ml). 1M sodium methoxide in methanol (1.5 ml)was added and the reaction mixture was stirred for 2 h. TFA (0.2 ml) wasadded and the mixture concentrated in vacuo. The residue was purified byHPLC (C18/MeCN:H2O:0.1% TFA). Freezedrying afforded a white solid whichwas dissolved in pyridine (5 ml). Acetic anhydride (1 ml) was added andthe reaction mixture was stirred at rt 5 h followed by removal ofsolvents in vacuo, the residue was dissolved in small amount ofdichloromethane and filtered through a plug of silica. The solvent wasremoved in vacuo to afford S10 a white solid (84 mg).

¹H NMR (400 MHz, Methanol-d₄) δ 8.58 (d, J=1.2 Hz, 2H), 7.60 (dd, J=8.5,6.5 Hz, 4H), 4.90 (d, J=3.3 Hz, 4H), 4.72 (t, J=10.1 Hz, 2H), 4.16 (d,J=2.8 Hz, 2H), 3.94-3.78 (m, 4H), 3.72 (dd, J=11.3, 4.4 Hz, 2H).

Experimental Section 2 Evaluation of Kd Values

The affinity of compounds 3a-c for galectins were determined by afluorescence anisotropy assay where the compound was used as aninhibitor of the interaction between galectin and a fluorescein taggedsaccharide probe as described Sörme, P., Kahl-Knutsson, B., Huflejt, M.,Nilsson, U. J., and Leffler H. (2004) Fluorescence polarization as ananalytical tool to evaluate galectin-ligand interactions. Anal. Biochem.334: 36-47 (Sörme et al., 2004) and Monovalent interactions ofGAlectin-1 By Salomonsson, Emma; Larumbe, Amaia; Tejler, Johan;Tullberg, Erik; Rydberg, Hanna; Sundin, Anders; Khabut, Areej; Frejd,Torbjorn; Lobsanov, Yuri D.; Rini, James M.; et al, From Biochemistry(2010), 49(44), 9518-9532, (Salomonsson et al. 2010). The assay wasadapted to be able to measure the high affinity of the present compoundfor galectin-3 by using a probe (SY) constructed to have high affinityfor galectin-3 based on the structure of3,3′-dideoxy-3,3′-di-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosidewhich made it possible to use a low concentration of galectin-3 (50 nM).100 nM albumin was included as a carrier to prevent protein loss at suchlow concentration of galectin.

Kd values for compounds 3a-c and reference compound3,3′-Dideoxy-3,3′-di-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(SX)

Galectin-1 Galectin-3 Example Kd (μM) Kd (μM) 3a 0.078 0.003 3b 0.0790.001 3c 0.110 0.002 SX 0.060 0.001

Materials and Methods

NMR spectra were recorded on a Bruker Avance II 400 MHz spectrometer atambient temperature. ¹H-NMR spectra were assigned using 2D-methods(COSY). Chemical shifts are given in ppm downfield from the signal forMe₄Si, with reference to residual CHCl₃ or CD₂HOD. HRMS was recorded ona Micromass Q-TOF micro spectrometer (ESI). Reactions were monitored byTLC using aluminum-backed silica gel plates (Merck 60F₂₅₄) andvisualized using UV light and by chaffing with ethanolic H₂SO₄ (7%).Column chromatography was performed using silica gel (40-60 μm, 60 Å).Solvents were dried by storing over activated M.S. Reagents weresupplied by Sigma-Aldrich and used as it is.

Synthesis

Experimental Procedures Example 1.12,2′,4,4′,6,6′-Hexa-O-acetyl-3,3′-dideoxy-3,3′-di-[4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside2a

To a mixture of A1 (300 mg, 0.45 mmol) (van Scherpenzeel, M.; Moret, E.E.; Ballell, L.; Liskamp, R. M. J.; Nilsson, U. J.; Leffler, H.;Pieters, R. J. Synthesis and Evaluation of New Thiodigalactoside-BasedChemical Probes to Label Galectin-3. ChemBioChem 2009, 10, 1724-1733)and CuI (17 mg, 0.091 mmol) in acetonitrile (30 mL) was3,4-difluorophenylacetylene (0.14 mL, 1.14 mmol) added followed bydiisopropylethylamine (0.079 mL, 0.45 mmol). The resulting mixture wasstirred at 50° C. for 8 h. The reaction was quenched with sat. aq. NH₄Cland the solvent was evaporated. Water was added to the residue andextracted twice with CH₂Cl₂; the organic phases were washed with brine,dried and evaporated. The obtained residue was purified by columnchromatography (heptane:EtOAc 1:1->1:4) to give 2a (115 mg, 23%).

¹H-NMR (CDCl₃, 400 MHz) δ 7.98 (s, 2H), 7.73 (td, J=9.5, 2.1 Hz, 2H),7.60 (m, 2H), 7.21 (t, J=7.6 Hz, 2H), 5.88 (t, J=9.7 Hz, 2H), 5.62 (d,J=2.3 Hz, 2H), 5.16 (dd, J=11.1, 3.1 Hz, 2H), 4.89 (d, J=9.6 Hz, 2H),4.55 (dd, J=11.6, 7.0 Hz, 2H), 4.20 (t, J=6.6 Hz, 2H), 4.05 (dd, J=11.7,5.0 Hz, 2H), 2.15 (s, 6H), 2.13 (s, 6H), 1.92 (s, 6H).

Example 2.12,2′,4,4′,6,6′-Hexa-O-acetyl-3,3′-bisdeoxy-3,3′-bis-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside2b

To a mixture of A1 (300 mg, 0.45 mmol) and CuI (17 mg, 0.091 mmol) inacetonitrile (20 mL) was 3,4,5-trifluorophenylacetylene (0.086 mL, 0.72mmol) added followed by diisopropylethylamine (0.079 mL, 0.45 mmol). Theresulting mixture was stirred at 50° C. for 6 h. The reaction wasquenched with sat. aq. NH₄Cl and the solvent was evaporated. Water wasadded to the residue and extracted twice with CH₂Cl₂; the organic phaseswere washed with brine, dried and evaporated. The obtained residue waspurified by column chromatography (heptane:EtOAc 1:1->1:4) to give 2b(28 mg, 6%).

¹H-NMR (CDCl₃, 400 MHz) δ 8.12 (s, 2H), 7.60 (dd, J=8.3, 6.4 Hz, 4H),5.95 (dd, J=11.0 9.5 Hz, 2H), 5.62 (d, J=2.7 Hz, 2H), 5.13 (dd, J=11.0,3.3 Hz, 2H), 4.81 (d, J=9.5 Hz, 2H), 4.74 (dd, J=12.6, 7.4 Hz, 2H), 4.23(m, 2H), 3.98 (dd, J=11.7, 4.1 Hz, 2H), 2.20 (s, 6H), 2.15 (s, 6H), 1.92(s, 6H).

Example 3.12,2′,4,4′,6,6′-Hexa-O-acetyl-3,3′-bisdeoxy-3,3′-bis-[4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside2c

To a mixture of A1 (505 mg, 0.76 mmol) and CuI (77 mg, 0.40 mmol) inacetonitrile (30 mL) was 3,5-difluorophenylacetylene (0.224 mL, 1.89mmol) added followed by diisopropylethylamine (0.132 mL, 0.76 mmol). Theresulting mixture was stirred at r.t. for 2 h. The reaction was quenchedwith brine and the mixture was extracted with Et₂O. The organic phasewas washed once with brine and the combined water phases extracted oncewith Et₂O. The combined organic phases were dried (Na₂SO₄) andevaporated. The obtained residue 2c was used without furtherpurification in next step.

ESI-MS m/z calcd for [C₄₀H₄₁F₄N₆O₁₄S]⁺, (M+H)⁺, 937.2; found: 937.2.

Example 4.13,3′-dideoxy-3,3′-di-[4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside3a

NaOMe (1 M, 3 mL) was added to a stirred solution of 2a (115 mg, 0.12mmol) in MeOH (12 mL) and CH₂Cl₂ (3 mL). After 18 hours was the solutionadjusted to pH 7 by Dowex and concentrated. The residue was purified bycolumn chromatography (CH₂Cl₂:MeOH 19:1->4:1) to give 3a (36 mg, 43%).

¹H-NMR (MeOD, 400 MHz) δ 8.55 (s, 2H), 7.72 (ddd, J=11.5, 7.6, 2.1 Hz,2H), 7.60 (m, 2H), 7.30 (td, J=10.4, 7.6 Hz, 2H), 4.92 (obscured bywater, 4H), 4.77 (t, J=9.8 Hz, 2H), 4.16 (d, J=2.6 Hz, 2H), 3.90 (m,2H), 3.83 (m, 2H), 3.72 (dd, J=11.5, 4.4 Hz, 2H).

HRMS calcd for [C₂₈H₂₉N₆O₈F₄S]⁺, 685.1704; found: 685.1696.

Example 5.13,3′-bisdeoxy-3,3′-bis-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside3b

NaOMe (1 M, 2 mL) was added to a stirred solution of 2b (28 mg, 0.029mmol) in MeOH (4 mL) and CH₂Cl₂ (1 mL). After 3 days was the solutionadjusted to pH 7 by Dowex and concentrated. The residue was purified bycolumn chromatography (CH₂Cl₂:MeOH 19:1->9:1) to give 3b (14 mg, 68%).

¹H-NMR (MeOD, 400 MHz) δ 8.59 (s, 2H), 7.60 (dd, J=8.7, 6.6 Hz, 4H),4.92 (obscured by water, 4H), 4.72 (t, J=9.7 Hz, 2H), 4.16 (d, J=2.7 Hz,2H), 3.90 (m, 2H), 3.83 (m, 2H), 3.72 (dd, J=11.4, 4.4 Hz, 2H).

HRMS calcd for [C₂₈H₂₇N₆O₈F₆S]⁺, 721.1515; found: 721.1514.

Example 6.13,3′-bisdeoxy-3,3′-bis-[4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside3c

NaOMe (183 mg, 3.39 mmol) was added to a stirred solution of 2c (0.76mmol, crude from previous step) in MeOH (40 mL) and CH₂Cl₂ (10 mL).After 18 hours was the solution adjusted to pH 7 by AcOH andconcentrated. The residue was purified by column chromatography(EtOAc:MeOH 10:1) and re-crystalized from MeCN to give 3c in 27% yieldover two steps.

¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (s, 2H), 7.65-7.56 (m, 4H), 7.19 (tt,J=9.4, 2.5 Hz, 2H), 5.38 (dd, J=6.8, 2.0 Hz, 4H), 4.94 (d, J=9.5 Hz,2H), 4.87 (dd, J=10.6, 3.0 Hz, 2H), 4.71 (t, J=5.7 Hz, 2H), 4.15-4.26(m, 2H), 3.98 (dd, J=6.6, 3.0 Hz, 2H), 3.74 (t, J=6.3 Hz, 2H), 3.47-3-63(m, 4H).

ESI-MS m/z calcd for [C₂₈H₂₉N₆O₈F₄S]⁺, (M+H)⁺, 685.2; found: 685.0.

REFERENCES

-   Almkvist, J., Fäldt, J., Dahlgren, C., Leffler, H., and    Karlsson, A. (2001) Lipopolysaccharide-induced gelatinase granule    mobilization primes neutrophils for activation by galectin-3 and    f-Met-Leu-Phe. Infect. Immun. Vol. 69: 832-837.-   Barondes, S. H., Cooper, D. N. W., Gitt, M. A., and Leffler, H.    (1994). Galectins. Structure and function of a large family of    animal lectins. J. Biol. Chem. 269:20807-20810.-   Blois, S. M., Ilarregui, J. M., Tometten, M., Garcia, M., Orsal, A.    S., Cordo-Russo, R., Toscano, M. A., Bianco, G. A., Kobelt, P.,    Handjiski, B., et al. (2007). A pivotal role for galectin-1 in    fetomaternal tolerance. Nat Med 13: 1450-1457.-   Chen, W.-S., Leffler H., Nilsson, U. J., Panjwani, N. (2012).    Targeting Galectin-1 and Galectin-3 Attenuates VEGF-A-induced    Angiogenesis; Mol. Biol. Cell (suppl), Abstract No. 2695.-   Cumpstey, I., Carlsson, S., Leffler, H. and Nilsson, U. J. (2005)    Synthesis of a phenyl thio-β-D-galactopyranoside library from    1,5-difluoro-2,4-dinitrobenzene: discovery of efficient and    selective monosaccharide inhibitors of galectin-7. Org. Biomol.    Chem. 3: 1922-1932.-   Cumpstey, I., Sundin, A., Leffler, H. and Nilsson, U. J. (2005)    C₂-Symmetrical thiodigalactoside bis-benzamido derivatives as    high-affinity inhibitors of galectin-3: Efficient lectin inhibition    through double arginine-arene interactions. Angew. Chem. Int. Ed.    44: 5110-5112.-   Cumpstey, I., Salomonsson, E., Sundin, A., Leffler, H. and    Nilsson, U. J. (2008) Double affinity amplification of    galectin-ligand interactions through arginine-arene interactions:    Synthetic, thermodynamic, and computational studies with aromatic    diamido-thiodigalactosides. Chem. Eur. J. 14: 4233-4245.-   Dam, T. K., and Brewer, C. F. (2008). Effects of clustered epitopes    in multivalent ligand-receptor interactions. Biochemistry 47:    8470-8476.-   Delacour, D., Greb, C., Koch, A., Salomonsson, E., Leffler, H., Le    Bivic, A., and Jacob, R. (2007). Apical Sorting by    Galectin-3-Dependent Glycoprotein Clustering. Traffic 8: 379-388.-   Delaine, T., Cumpstey, I., Ingrassia, L., Le Mercier, M., Okechukwu,    P., Leffler, H., Kiss, R., and Nilsson, U. J. (2008).    Galectin-Inhibitory Thiodigalactoside Ester Derivatives Have    Anti-Migratory Effects in Cultured Lung and Prostate Cancer Cells. J    Med Chem 51; 8109-8114.-   Garner, O. B., and Baum, L. G. (2008). Galectin-glycan lattices    regulate cell-surface glycoprotein organization and signalling.    Biochem Soc Trans 36: 1472-1477.-   Giguere, D., Patnam, R., Bellefleur, M.-A., St.-Pierre, C., Sato,    S., and Roy, R. (2006). Carbohydrate triazoles and isoxazoles as    inhibitors of galectins-1 and -3. Chem Commun: 2379-2381.-   Glinsky, G. V., Price, J. E., Glinsky, V. V., Mossine, V. V.,    Kiriakova, G., and Metcalf, J. B. (1996). Cancer Res 56: 5319-5324.-   Glinsky, V. V., Kiriakova, G., Glinskii, O. V., Mossine, V. V.,    Mawhinney, T. P., Turk, J. R., Glinskii, A. B., Huxley, V. H.,    Price, J. E., and Glinsky, G. V. (2009). Synthetic Galectin-3    Inhibitor Increases Metastatic Cancer Cell Sensitivity to    Taxol-Induced Apoptosis In Vitro and In Vivo. Neoplasia 11; 901-909.-   Huflejt, M. E. and Leffler, H. (2004) Galectin-4 in normal tissues    and cancer. Glycoconj. J. 20: 247-255.-   Ingrassia et al. (2006) A Lactosylated Steroid Contributes in Vivo    Therapeutic Benefits in Experimental Models of Mouse Lymphoma and    Human Glioblastoma. J. Med. CHem. 49: 1800-1807.-   John, C. M., Leffler, H., Kahl-Knutsson, B., Svensson, I., and    Jarvis, G. A. (2003) Truncated Galectin-3 Inhibits Tumor Growth and    Metastasis in Orthotopic Nude Mouse Model of Human Breast Cancer.    Clin. Cancer Res. 9: 2374-2383.-   Lau, K. S., and Dennis, J. W. (2008). N-Glycans in cancer    progression. Glycobiology 18: 750-760.-   Lau, K. S., Partridge, E. A., Grigorian, A., Silvescu, C. I.,    Reinhold, V. N., Demetriou, M., and Dennis, J. W. (2007). Complex    N-glycan number and degree of branching cooperate to regulate cell    proliferation and differentiation. Cell 129: 123-134.-   Leffler, H. and Barondes, S. H. (1986) Specificity of binding of    three soluble rat lung lectins to substituted and unsubstituted    mammalian beta-galactosides. J. Biol. Chem. 261:10119-10126.-   Leffler, H. Galectins Structure and Function—A Synopsis in Mammalian    Carbohydrate Recognition Systems (Crocker, P. ed.) Springer Verlag,    Heidelberg, 2001 pp. 57-83.-   Leffler, H., Carlsson, S., Hedlund, M., Qian, Y. and    Poirier, F. (2004) Introduction to galectins. Glycoconj. J. 19:    433-440.-   Leffler, H., editor, (2004b) Special Issue on Galectins.    Glycoconj. J. 19: 433-638.-   Lin, C.-I., Whang, E. E., Donner, D. B., Jiang, X., Price, B. D.,    Carothers, A. M., Delaine, T., Leffler, H., Nilsson, U. J., Nose,    V., et al. (2009). Galectin-3 Targeted Therapy with a Small Molecule    Inhibitor Activates Apoptosis and Enhances Both Chemosensitivity and    Radiosensitivity in Papillary Thyroid Cancer. Mol Cancer Res 7:    1655-1662.-   MacKinnon, A. C., Farnworth, S. L., Henderson, N. C., Hodkinson, P.    S., Kipari, T., Leffler, H., Nilsson, U. J., Haslett, C., Hughes,    J., and Sethi T. (2008). Regulation of alternative macrophage    activation by Galectin-3. J. Immun. 180; 2650-2658.-   Mackinnon, A., Gibbons, M., Farnworth, S., Leffler, H., Nilsson, U.    J., Delaine, T., Simpson, A., Forbes, S., Hirani, N., Gauldie, J.,    and Sethi T. (2012). Regulation of TGF-β1 driven lung fibrosis by    Galectin-3. Am. J. Resp. Crit. Care Med., in press.-   Massa, S. M., Cooper, D. N. W., Leffler, H., Barondes, S. H. (1993)    L-29, an endogenous lectin, binds to glycoconjugate ligands with    positive cooperativity. Biochemistry 32: 260-267.-   Partridge, E. A., Le Roy, C., Di Guglielmo, G. M., Pawling, J.,    Cheung, P., Granovsky, M., Nabi, I. R., Wrana, J. L., and    Dennis, J. W. (2004). Regulation of cytokine receptors by Golgi    N-glycan processing and endocytosis. Science 306: 120-124.-   Perone, M. J., Bertera, S., Shufesky, W. J., Divito, S. J.,    Montecalvo, A., Mathers, A. R., Larregina, A. T., Pang, M., Seth,    N., Wucherpfennig, K. W., et al. (2009). Suppression of autoimmune    diabetes by soluble galectin-1. J Immunol 182: 2641-2653.-   Pienta, K. J., Naik, H., Akhtar, A., Yamazaki, K., Reploge, T. S.,    Lehr, J., Donat, T. L., Tait, L., Hogan, V., and Raz, A. (1995).    Inhibition of spontaneous metastasis in a rat prostate cancer model    by oral administration of modified citrus pectin. J Natl Cancer Inst    87, 348-353.-   Saegusa, J., Hsu, D. K., Chen, H. Y., Yu, L., Fermin, A., Fung, M.    A., and Liu, F. T. (2009). Galectin-3 is critical for the    development of the allergic inflammatory response in a mouse model    of atopic dermatitis. Am J Pathol 174: 922-931.-   Salameh, B. A., Leffler, H. and Nilsson, U. J. (2005) Bioorg. Med.    Chem. Lett. 15: 3344-3346.-   Salameh, B. A., Cumpstey, I., Sundin, A., Leffler, H., and    Nilsson, U. J. (2010). 1H-1,2,3-Triazol-1-yl thiodigalactoside    derivatives as high affinity galectin-3 inhibitors. Bioorg Med Chem    18: 5367-5378.-   Salomonsson, E., Larumbe, A., Tejler, J., Tullberg, E., Rydberg, H.,    Sundin, A., Khabut, A., Frejd, T., Lobsanov, Y. D., Rini, J. M.,    Nilsson, U. J., and Leffler, H (2010). Monovalent interactions of    galectin-1. Biochemistry 49: 9518-9532.-   Sörme, P., Qian, Y., Nyholm, P.-G., Leffler, H.,    Nilsson, U. J. (2002) Low micromolar inhibitors of galectin-3 based    on 3′-derivatization ofN-acetyllactosamine. ChemBioChem 3:183-189.-   Sörme, P., Kahl-Knutsson, B., Wellmar, U., Nilsson, U. J., and    Leffler H. (2003a) Fluorescence polarization to study    galectin-ligand interactions. Meth. Enzymol. 362: 504-512.-   Sörme, P., Kahl-Knutsson, B., Wellmar, U., Magnusson, B.-G., Leffler    H., and Nilsson, U. J. (2003b) Design and synthesis of galectin    inhibitors. Meth. Enzymol. 363: 157-169.-   Sörme, P., Kahl-Knutsson, B., Huflejt, M., Nilsson, U. J., and    Leffler H. (2004) Fluorescence polarization as an analytical tool to    evaluate galectin-ligand interactions. Anal. Biochem. 334: 36-47.-   Thijssen, V. L., Poirer, F., Baum, L. G., and Griffioen, A. W.    (2007). Galectins in the tumor endothelium: opportunities for    combined cancer therapy. Blood 110: 2819-2827.-   Toscano, M. A., Bianco, G. A., Ilarregui, J. M., Croci, D. O.,    Correale, J., Hernandez, J. D., Zwirner, N. W., Poirier, F.,    Riley, E. M., Baum, L. G., et al. (2007). Differential glycosylation    of TH1, TH2 and TH-17 effector cells selectively regulates    susceptibility to cell death. Nat Immunol 8: 825-834.

1. A compound of formula (1)

Wherein A is selected from

wherein R₁-R₃ are independently selected from hydrogen (H), fluorine,methyl optionally substituted with a fluorine (F), and OCH₃ optionallysubstituted with a F; R₄ and R₅ are independently selected from H, F, Cland methyl; R₆ is selected from C₁₋₆ alkyl, branched C₃₋₆ alkyl and C₃₋₇cycloalkyl; R₇ is selected from aryl optionally substituted with a F,Cl, methyl optionally substituted with a F, and OCH₃ optionallysubstituted with a F; B is selected from

wherein R₈-R₁₂ are independently selected from H, F, methyl optionallysubstituted with a fluorine (F), and OCH₃ optionally substituted with aF; R₁₃-R₁₆ are independently selected from H, F, methyl optionallysubstituted with a F, and OCH₃ optionally substituted with a F; R₁₇ isselected from C₁₋₆ alkyl, branched C₃₋₆ alkyl and C₃₋₇ cycloalkyl; R₁₈is selected from aryl optionally substituted with a F, Cl, methyloptionally substituted with a F, and OCH₃ optionally substituted with aF; or a pharmaceutically acceptable salt or solvate thereof.
 2. Thecompound of claim 1 with the proviso that A and B cannot be identical.3. The compound of claim 1 wherein A is selected from formula 2 and B isselected from formula
 6. 4. The compound of claim 3 wherein R₁-R₃ areindependently selected from H or F, and wherein R₈-R₁₂ are independentlyselected from H or F.
 5. The compound of claim 1 wherein A is selectedfrom formula 2 and B is selected from
 7. 6. The compound of claim 5wherein R₁-R₃ are independently selected from H or F, and whereinR₁₃-R₁₄ are both F, and R₁₅-R₁₆ are both H.
 7. The compound of claim 6wherein R₁ is H, R₂ is H, and R₃ is F.
 8. The compound of claim 6wherein R₁-R₃ are F.
 9. The compound of claim 1 wherein A is selectedfrom formula 2 and B is selected from
 8. 10. The compound of claim 9wherein R₁-R₃ are independently selected from H or F, and R₁₇ is C₁₋₅alkyl.
 11. The compound of claim 9 wherein R₁-R₃ are all F, and R₁₇ istert-butyl or n-butyl.
 12. The compound of claim 1 wherein A is selectedfrom formula 2 and B is selected from
 9. 13. The compound of claim 12wherein R₁-R₃ are independently selected from H or F, and R₁₈ isselected from phenyl substituted with four F and one OCH₃, such as2,3,5,6-tetrafluoro-4-methoxy-phenyl; 2-anthracenyl; 9-anthracenyl;1-Naphtyl and 2-Naphtyl.
 14. The compound of claim 12 wherein R₁-R₃ areall F, and R₁₈ is selected from 2,3,5,6-tetrafluoro-4 methoxy-phenyl.15. The compound of claim 1 which is a compound of formula (I)

wherein R_(a)-R_(f) are independently selected from fluorine orhydrogen, and at least three of R_(a)-R_(f) are F and the remaining areH, or all of R_(a)-R_(f) are F.
 16. The compound of claim 1 which isselected from3′-Deoxy-3-O-[(5,6-difluoro-2-oxo-3-chromenyl)methyl]-3′-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,3′-Deoxy-3-O-[(5,6-difluoro-2-oxo-3-chromenyl)methyl]-3′-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,3′-{4[(Butylamino)carbonyl]-1H-1,2,3-triazol-1-yl}deoxy-3-O-[(5,6-difluoro-2-oxo-3-chromenyl)methyl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,3-{4-[(Butylamino)carbonyl]-1H-1,2,3-triazol-1-yl}-3,3′-dideoxy-3′-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,3,3′-Dideoxy-3′-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-(4-methoxy-2,3,5,6-tetrafluoro-benzamido)-1,1′-sulfanediyl-di-β-D-galactopyranoside,3-(9-anthracenecarboxamide)-3,3′-Dideoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,3-(2-anthracenecarboxamide)-3,3′-Dideoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,3,3′-Dideoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-3′-[4-phenyl-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,3,3′-dideoxy-3,3′-di-[4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,3,3′-bisdeoxy-3,3′-bis-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside,and3,3′-bisdeoxy-3,3′-bis-[4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside.17. (canceled)
 18. A composition comprising the compound of claim 1 andoptionally a pharmaceutically acceptable additive, such as carrier orexcipient. 19-20. (canceled)
 21. A method for treatment of a disorderrelating to the binding of a galectin, such as galectin-3, to a ligandin a mammal, such as a human, wherein a therapeutically effective amountof at least one compound according to claim 1 is administered to amammal in need of said treatment.
 22. The method of claim 21, whereinsaid disorder is selected from the group consisting of inflammation;fibrosis, e.g. pulmonary fibrosis, or any solid organ fibrosis e.g.liver fibrosis, kidney fibrosis, ophtalmological fibrosis and fibrosisof the heart; septic shock; cancer; autoimmune diseases; metabolicdisorders; heart disease; heart failure; pathological angiogenesis, suchas ocular angiogenesis or a disease or condition associated with ocularangiogenesis, e.g. neovascularization related to cancer; and eyediseases, such as age-related macular degeneration and cornealneovascularization.